MicroRNA-18a在结肠癌HCT116细胞中对ATM基因表达和自噬的调控作用
|
摘要
背景：自噬是细胞通过自噬囊泡的形成和溶酶体的参与下对胞质内长寿命蛋白或者受损细胞器（如：内质网、高尔基体和线粒体）降解的过程，实现一些氨基酸和蛋白质的回收和利用。细胞生长过程存在一定的基础水平的自噬，作为细胞内的清理系统来维持细胞的稳态。在多种应激的条件下（如：饥饿、氧应激或者细胞毒性以及病原体感染），会激活自噬。在多种的生理或者生理病理过程中，会出现自噬的下调，如衰老、肿瘤和神经退行性变疾病。在肿瘤形成过程，自噬具有抑制肿瘤形成和促进肿瘤形成的双向的作用，主要取决于细胞背景的不同。自噬的双向作用现象同样存在于放疗和化疗过程中。有报道，因自噬支持癌细胞在不利的条件下的生存而产生抵抗治疗的作用。在其他情况下，诱导自噬会导致肿瘤细胞死亡（也被称为II型程序性细胞死亡），从而增强肿瘤放、化疗的治疗效果。因此，对自噬分子机更多的了解和适合体外应用的自噬调控因素的发现将显著的有益于临床肿瘤的治疗。最近，一个重要基因（Ataxia telangiectasia mutated，ATM）发现对自噬具有调控作用。ATM是一个丝氨酸/苏氨酸蛋白激酶，属于PIKK（phosphoinositide3-kinase-related protein kinase family，PIKK）蛋白激酶家族成员。在电离辐射引起的DNA损伤的情况下，ATM通过一系列的调控会诱导细胞周期阻滞、凋亡和DNA修复等，维持基因组的稳定。最近，ATM被发现在细胞毒性或者活性氧应激的情况下，上调自噬进程。ATM通过激活AMPK/LKB1/TSC2信号通路，抑制自噬网络中的关键基因mTORC1(mammalian target ofrapamycine complex1)的表达而激活自噬。因此，通过化学或者基因技术调控ATM来调控自噬进程成为肿瘤研究的热点。MicroRNA（miRNA）是一类短的单链非编码的RNA分子（20~22核苷酸）。miRNA是DNA转录形成发夹环状结构的前体pre-miRNA(60–110核苷酸)，从细胞核转运到细胞质中经过过剪切成为成熟的miRNA。miRNA通过与靶基因mRNA的3’UTR（3'-untranslated region）结合抑制基因的转录后翻译而抑制基因的表达。据预测，哺乳动物中有60%的编码基因受到miRNA的调控。汇总当前miRNA的研究成果，miNRAs几乎对所有的细胞进程具有调控作用，如分化、生长、凋亡等。MiRNA表达谱的改变与人类疾病，尤其肿瘤密切相关。MiRNAs通过与自噬相关基因（autophagy-regulating genes，Atgs）的调控也参与自噬进程的调控。MiR-30a和miR-376b被证明通过抑制靶基因Beclin-1的激活而抑制自噬。MiR-101通过抑制在自噬体形成早期阶段发挥作用的基因RAB5A抑制自噬。
目的：尽管，microRNA-自噬相互作用的研究领域还处在初始阶段，但是这一领域的研究，帮助我们对自噬有更深层分子调控机制的理解和提供将来应用治疗的前景。本研究目的寻找有效调控ATM的miRNA，并进一步的研究其对基础水平和电离辐射诱导的自噬的影响。
方法：（1）通过生物信息学预测工具预测以ATM为靶基因的miRNAs；（2）PCR调取含有预测的miR-18a结合位点的部分ATM基因3’UTR序列，构建在荧光素酶载体；（3）双荧光素酶报告基因分析验证miR-18a与靶基因3’UTR的结合；（4）深部X射线治疗机进进行细胞放射治疗；（5）Western blot检测基因蛋白水平的变化；（6）应用qRT-PCR的方法检测细胞内miRNA的表达情况；（7）应用GFP-LC3定位分析和MAP1LC3的Western blot监测自噬进程；（8）集落形成实验验证细胞的电离辐射敏感性；（9）Cellcounting Kit-8（CCK8）试剂盒分析细胞增殖活性；（10）应用Student’s t-test或χ2检验统计分析，p<0.05表示差异有统计学意义；（11）Image J软件分析蛋白电泳条带值。
结果：
1. MiR-18a与ATM3’UTR有潜在的结合
根据三个生物信息学预测工具(Miranda, Targetscan, andmiRDB)，ATM是miR-18a的靶基因。人类和其他哺乳类动物(包括黑猩猩、恒河猴、小鼠、大鼠、狗和兔)的ATM3’UTR序列均存在非常保守的miR-18a结合靶点（人类ATM3'-UTR上的3481-3488位置）。
2. MiR-18a结合并上调ATM基因的表达
经双荧光素酶报告基因分析，惊奇的发现在结肠癌HCT116细胞中，miR-18a上调ATM3’-UTR荧光素酶载体表达活性。与ATM3’-UTR荧光素酶载体共转染的miR-18amimic和NC组的荧光素酶值分别为90%和30%(**P<0.01)。应用慢病毒载体PCDH-vector构建的miR-18a表达载体验证也获得了相似的结果(*P<0.05)。经蛋白电泳检测，电离辐射（4Gy）增加HCT116细胞ATM蛋白的表达（1.6倍）。与转染NC（Negative control）比，转染miR-18a mimic后HCT116细胞ATM蛋白的表达升高1.6倍。而抑制miR-18a表达后，同时联合或者不联合电离辐射，HCT116细胞中ATM的表达都减低近50%。
3.电离辐射上调细胞内miR-18a的表达
qRT-PCR检测，电离辐射1h后，内源性miR-18a的表达升高超过200倍。电离辐射后7h，miR-18a的表达水平比假照组高出5倍。表明miR-18a的表达随着电离辐射作用后时间变化而变化。上述结果表明，miR-18a可能在电离辐射诱导的细胞反应中（例如自噬）发挥一定作用。
4.过表达miR-18a促进HCT116细胞的自噬
构建稳定表达的HCT116GFP-LC3细胞模型，分析miR-18a对HCT116细胞自噬的影响。HCT116GFP-LC3细胞转染NC组自噬阳性的细胞8%，过表达miR-18a的mimics组自噬升高，自噬阳性的细胞达15%(**P <0.01)。蛋白电泳检测LC3-II的变化，与对照组比较，电离辐射使LC3-II升高3.5倍，转染miR-18a mimic组LC3-II的表达升高2倍。P62/SQSTM1多聚泛素结合蛋白，与ATG8/LC3结合并定位在自噬体，最终被降解。P62/SQSTM1蛋白的表达水平反应自噬的量。在过表达miR-18a组和过表达miR-18a联合照射组，P62/SQSTM1的表达水平比转染NC组减低近50%。这些结果表明，miR-18a在HCT116细胞中增加自噬通量（autophagicflux）。
5.过表达miR-18a抑制mTORC1活性
据报道ATM通过抑制mTORC1的表达上调自噬。我们推测miR-18a上调ATM的表达，应该抑制mTORC1进而激活自噬。通过蛋白电泳检测mTORC1下游一个典型的反映其活性的蛋白，P70S6K的Thr389位点磷酸化情况。结果，转染miR-18a mimic或者转染mimic联合照射后，P70S6K蛋白的Thr389位点磷酸化都明显的受到抑制。
6过表达miR-18a增加HCT116细胞的电离辐射敏感性
集落形成分析表明，与转染NC各组比较，转染miR-18a mimic后4Gy、6Gy和8Gy明显的降低细胞存活分数（分别为*P<0.05，*P<0.05和**P<0.01）。
7过表达miR-18a后抑制结肠癌细胞的增殖。CCK-8分析表明，与转染NC组比较，过表达miR-18a后显著抑制了HCT116和SW116细胞的增殖，细胞增殖活性降低到近70%（**P<0.01）。而抑制miR-18a则促进HCT116细胞株的增殖(**P<0.01)。
结论：
1ATM基因是miR-18a新的靶基因，但在HCT116细胞中过表达miR-18a升高ATM基因的表达（在电离辐射前和电离辐射后）。这样现象可能是miR-18a对ATM基因3’UTR结合、调控所致，且依赖于不同的细胞背景。
2HCT116细胞中过表达miR-18a可以直接激活基础水平的自噬和增强电离辐射诱导的自噬，致少是部分通过上调自噬调控基因ATM发挥的作用。过表达miR-18a后，通过检测P70S6K蛋白Thr389位点磷酸化受到抑制的情况表明，miR-18a抑制mTORC1的活性，支持miR-18a上调ATM的结论。
3过表达miR-18a增加HCT116细胞对电离辐射的敏感性。
4在结肠癌中miR-18a是发挥抑癌作用的miRNA。
综上所述，本研究揭示miR-18a新的重要的靶基因ATM和miR-18a新的功能，在细胞关键性事件自噬中发挥作用。miR-18a对ATM和自噬的调控作用在肿瘤的发生、发展、治疗以及其他的疾病中会发挥重要作用。因此，miR-18a是结肠癌表观遗传学治疗很好的靶点。
Autophagy is a cellular self-catabolic degradation process whichworks to optimize the bio-energetic cellular microenvironment bydegrading cytoplasmic components such as long-lived proteins anddamaged organelles. Autophagy is active at basal cellular growth levels towork as an endogenous cleaning system, and also can be triggered bydiverse stressful conditions, such as adaptation to starvation, oxidative orgenotoxic stress, and elimination of pathogens. And thus deregulatedautophagy has been observed in various physiological and patho-physiological processes, including aging, cancer and neurodegenerativediseases. The exact role of autophagy in carcinogenesis remains elusive.Autophagy shows dual roles during tumorigenesis as it can behave as atumor suppressor or oncogene depending on the cell context. A similarparadox is exhibited during tumor radio-or chemotherapy therapy,wherein autophagy has been reported to support cancer cell survival and thereby reduce efficacy of the cancer treatment. However, in othercontexts, induction of autophagy has been shown to contribute to cancercell death (also known as programmed cell death type–II) andconsequently enhance therapeutic efficacy of tumor radio-orchemotherapy. Therefore, achieving better molecular understanding ofautophagy and the discovery of specific autophagy modulators suitablefor in vivo use will help to dramatically improve cancer therapy. One ofthe major tumor suppressor genes that have been found recently tomodulate autophagy is ATM (Ataxia telangiectasia mutated). ATM is amulti-functional serine/threonine protein kinase which works to maintaingenomic stability by inducing cell cycle arrest, apoptosis, and DNA repairin response to DNA damage inducing agents particularly ionizingradiation (IR). Newly, ATM has been found to up-regulate autophagyprocess in response to genotoxic and oxidative stimuli. ATM suppressesthe activity of mammalian target of rapamycine complex1(mTORC1)through stimulating AMPK/LKB1/TSC2signaling pathway to ultimatelyinduce autophagy. Therefore, regulating ATM through chemical or genetic methods to modulate autophagy process has become an attractivepoint in cancer research. MicroRNAs are a short (~20–22nucleotideslong) single-stranded RNA molecules, non-coding, novel class of generegulators. They are synthesized from endogenous hairpin-shapedtranscripts (60–110nucleotide RNA precursor structures) in the nucleusthen exported to the cytoplasm. In the cytoplasm the mature microRNAstrand binds to the3'-untranslated region (3'-UTR) of the target mRNAto repress gene expression at the post-transcriptional level. In mammals,it is now predicted that microRNAs control the activity of more than60%of all protein-coding genes. The huge interest in the field of microRNAshas led to the conclusion that microRNAs take part in regulation ofalmost every cellular process known so far like development, growth,apoptosis, and the changes in expression of microRNAs are associatedwith many human disorders especially cancers. MicroRNAs have recentlybeen characterized as modulating the process of autophagy via thetargeting of cardinal autophagy-regulating genes. MiR-30a and miR-376bhave been demonstrated to target and inhibit Beclin-1activity, thereby blocking autophagy. Additionally, miR-101inhibits RAB5A, which actsin the early stages of autophagosome formation.
Objective: Although the field of microRNA-autophagy interrelationshipis still in its infancy, however exploring this filed could help us tounderstand in depth the molecular pathways that control autophagy andoffer future therapeutic perspectives. In our study we were interested todiscover a microRNA that could target ATM efficiently, and then studythe impact of that microRNA on autophagy process (basal and IR-induced autophagy).
Methods:
(1) Bioinformatics analysis was implemented to find a microRNA thatcould target ATM (2) PCR was used to acquire partial3’UTR fragmentand construct luciferase expression plasmids (3) Dual-LuciferaseReporter Assay was used to demonstrate the binding of selectedmicroRNA and ATM target gene (4) X-ray generator was utilized to deliver radiation (5) Western blot was used to analyze ATM proteinexpression level (6) qRT-PCR was used to detect endogenous miRNAexpression (7) GFP-LC3localization assay and LC3-II western blotassay to were used to monitor autophagy process (8) Clonogenic assaywas performed to study the changes in radiosensitivity (9) Cells viabilitywas evaluated by Cell counting Kit-8(10) Student t-test and χ2test wereused to determine statistical significance. P<0.01and P<0.05wereconsidered significant statistically (11) Image J software was used tocalculate the western blot band values.
Results:
1-Chose miR-18a that could bind to the3′-UTR of ATMVia intersecting results from three microRNA target prediction programs(Miranda, Targetscan, and miRDB), miR-18a was found to be a potentcandidate in all three algorithms for targeting ATM. As a putative targetgene, ATM has an extremely conserved single miR-18a target site(position3481-3488of human ATM3’-UTR) in human and other mammalian species, including the chimpanzee, rhesus monkey, mouse,rat, dog and rabbit.
2-miR-18a targets and upregulates ATM gene expression
During luciferase assay, surprisingly, in HCT116colon cancer cells, miR-18a mimic increased the expression of the reporter gene with the ATM3’-UTR tag to almost90%(**P<0.01) as compared to30%in negativecontrol (NC) transfected cells. Almost similar results (*P<0.05) wereobtained when luciferase assay was repeated using lentiviral PCDH-vector expressed miR-18a (PCDH-miR-18a). Western blot results showedthat miR-18a mimic led to1.6folds increase in ATM protein level innon-irradiated and1.7folds increase in4Gy irradiated HCT116cellsrelative to NC transfected cells. Moreover, inhibition of miR-18a led toalmost50%decrease in ATM expression level in irradiated and non-irradiated cells.
3-Endogenous miR-18a expression was up-regulated by ionizingradiation
q-RT-PCR results showed that expression level of endogenous miR-18adramatically increased to more than200folds one hour after exposure ofHCT116to IR. Seven hours after exposure to IR, miR-18a expressionlevel was just more than five folds above the basal level, indicating thatmiR-18a expression changes overtime after exposure to IR. Such resultssuggest that miR-18a could play role in IR-induced cellular events likeautophagy.
4-miR-18a overexpression promotes autophagy:
MiR-18a mimic significantly increased percentage of GFP-LC3puncta-positive cells to15%(**P <0.01) as compared to8%in NC transfectedcells and mock. Further more; the percentage of puncta-positive cellswas further increased up to25%when miR-18a mimic was combined with IR (**P <0.01), relative to cells treated with IR alone (15%).Consistent with GFP-LC3immunofluorescence, miR-18a mimic led tosharp increase in the LC3-II protein expression level in non-irradiated (2folds) and irradiated (3.5folds) HCT116cells as compared to NCtransfected counterparts. P62/SQSTM1is a poly-ubiquitin bindingprotein that was found to bind directly to ATG8/LC3and localize toautophagosomes to ultimately be degraded during autophagy. Therefore,the level of P62reflects the autophagic turnover. In the HCT116cellstransfected with miR-18a mimic, the expression level of theP62/SQSTM1protein was markedly reduced by almost50%in non-irradiated and irradiated cells as compared with the NC transfected cells.Consequently, such findings demonstrate that miR-18a overexpressionenhances the autophagic flux.
5-MiR-18a overexpression inhibits mTORC1activity
ATM has been demonstrated to upregulate autophagy via inhibition ofmTORC1. We hypothesized that miR-18a positively regulated ATM, inhibiting mTORC1and inducing autophagy. To examine whether miR-18a regulated mTORC1, we measured P70S6K phosphorylation atThr389as a typical readout of mTORC1activity by western blotting.MiR-18a mimic markedly decreased the phosphorylation of P70S6K atThr389in non-irradiated and irradiated HCT116cells (which indicatedmTORC1activity inhibition) as compared NC-transfected cells.
6-miR-18a overexpression enhances the radiosensitivity of HCT116cell line
Cologenic survival study showed that miR-18a mimic decreased thesurvival fraction of4,6, and8Gy irradiated HCT116cells (*P<0.05,*P<0.05and**P<0.01respectively) compared to NC transfected cells.
7-Ectopic miR-18a overexpression inhibits the growth of colon cancercells
CCK-8assay surprisingly showed that miR-18a mimic decreased the cell viability to almost70%in HCT116and SW116colon cancer cells(**P<0.01) as compared to NC transfected cells. On the other hand,inhibition of miR-18a increased cell viability (**P<0.01) of HCT116cellline.
Conclusions:
1-ATM is a novel target gene for miR-18a, and ectopic miR-18aoverexpression uniquely promotes ATM gene expression in HCT116colon cancer cells (pre and post-IR exposure). Such phenomena could beprobably through the direct impact of miR-18a on ATM3’UTR segment,which could be cell line-dependent phenomena.
2-Ectopic miR-18a overexpression results in strong induction of basaland IR-induced autophagy in HCT116cells, probably and at leastpartially through regulation of the expression of the known autophagyactivator ATM. This could be partially supported by finding that miR-18a overexpression could suppress mTORC1activity in HCT116cells, as indicated by decreased phosphorylation of P70S6K at Thr389in miR-18amimic transfected cells.
3-Exogenous overexpression of miR-18a enhances the radiationsensitivity of HCT116cells.
4-MiR-18a is a novel tumor suppressor microRNA in colon cancer. MiR-18a belongs to oncogenic miR-17-92cluster which encodes sixmicroRNAs (miR-17, miR-18a, miR-19a, miR-20a, miR-19b-1, and miR-92-1. All other members of this cluster have been previously reported toenhance colon cancer growth especially miR-92. This suggests that miR-18a opposes the oncogenic effect of miR-17-92cluster in colon cancer.In summary, results of the present study pertaining to the role of miR-18ain regulating ATM gene expression and autophagy process in coloncancer cells revealed a novel function for miR-18a in a critical cellularevent and on a crucial gene with significant impacts in cancerdevelopment, progression, treatment and in other diseases. Therefore,miR-18a is a good candidate for novel epigenetic colon cancer therapy.
目的：尽管，microRNA-自噬相互作用的研究领域还处在初始阶段，但是这一领域的研究，帮助我们对自噬有更深层分子调控机制的理解和提供将来应用治疗的前景。本研究目的寻找有效调控ATM的miRNA，并进一步的研究其对基础水平和电离辐射诱导的自噬的影响。
方法：（1）通过生物信息学预测工具预测以ATM为靶基因的miRNAs；（2）PCR调取含有预测的miR-18a结合位点的部分ATM基因3’UTR序列，构建在荧光素酶载体；（3）双荧光素酶报告基因分析验证miR-18a与靶基因3’UTR的结合；（4）深部X射线治疗机进进行细胞放射治疗；（5）Western blot检测基因蛋白水平的变化；（6）应用qRT-PCR的方法检测细胞内miRNA的表达情况；（7）应用GFP-LC3定位分析和MAP1LC3的Western blot监测自噬进程；（8）集落形成实验验证细胞的电离辐射敏感性；（9）Cellcounting Kit-8（CCK8）试剂盒分析细胞增殖活性；（10）应用Student’s t-test或χ2检验统计分析，p<0.05表示差异有统计学意义；（11）Image J软件分析蛋白电泳条带值。
结果：
1. MiR-18a与ATM3’UTR有潜在的结合
根据三个生物信息学预测工具(Miranda, Targetscan, andmiRDB)，ATM是miR-18a的靶基因。人类和其他哺乳类动物(包括黑猩猩、恒河猴、小鼠、大鼠、狗和兔)的ATM3’UTR序列均存在非常保守的miR-18a结合靶点（人类ATM3'-UTR上的3481-3488位置）。
2. MiR-18a结合并上调ATM基因的表达
经双荧光素酶报告基因分析，惊奇的发现在结肠癌HCT116细胞中，miR-18a上调ATM3’-UTR荧光素酶载体表达活性。与ATM3’-UTR荧光素酶载体共转染的miR-18amimic和NC组的荧光素酶值分别为90%和30%(**P<0.01)。应用慢病毒载体PCDH-vector构建的miR-18a表达载体验证也获得了相似的结果(*P<0.05)。经蛋白电泳检测，电离辐射（4Gy）增加HCT116细胞ATM蛋白的表达（1.6倍）。与转染NC（Negative control）比，转染miR-18a mimic后HCT116细胞ATM蛋白的表达升高1.6倍。而抑制miR-18a表达后，同时联合或者不联合电离辐射，HCT116细胞中ATM的表达都减低近50%。
3.电离辐射上调细胞内miR-18a的表达
qRT-PCR检测，电离辐射1h后，内源性miR-18a的表达升高超过200倍。电离辐射后7h，miR-18a的表达水平比假照组高出5倍。表明miR-18a的表达随着电离辐射作用后时间变化而变化。上述结果表明，miR-18a可能在电离辐射诱导的细胞反应中（例如自噬）发挥一定作用。
4.过表达miR-18a促进HCT116细胞的自噬
构建稳定表达的HCT116GFP-LC3细胞模型，分析miR-18a对HCT116细胞自噬的影响。HCT116GFP-LC3细胞转染NC组自噬阳性的细胞8%，过表达miR-18a的mimics组自噬升高，自噬阳性的细胞达15%(**P <0.01)。蛋白电泳检测LC3-II的变化，与对照组比较，电离辐射使LC3-II升高3.5倍，转染miR-18a mimic组LC3-II的表达升高2倍。P62/SQSTM1多聚泛素结合蛋白，与ATG8/LC3结合并定位在自噬体，最终被降解。P62/SQSTM1蛋白的表达水平反应自噬的量。在过表达miR-18a组和过表达miR-18a联合照射组，P62/SQSTM1的表达水平比转染NC组减低近50%。这些结果表明，miR-18a在HCT116细胞中增加自噬通量（autophagicflux）。
5.过表达miR-18a抑制mTORC1活性
据报道ATM通过抑制mTORC1的表达上调自噬。我们推测miR-18a上调ATM的表达，应该抑制mTORC1进而激活自噬。通过蛋白电泳检测mTORC1下游一个典型的反映其活性的蛋白，P70S6K的Thr389位点磷酸化情况。结果，转染miR-18a mimic或者转染mimic联合照射后，P70S6K蛋白的Thr389位点磷酸化都明显的受到抑制。
6过表达miR-18a增加HCT116细胞的电离辐射敏感性
集落形成分析表明，与转染NC各组比较，转染miR-18a mimic后4Gy、6Gy和8Gy明显的降低细胞存活分数（分别为*P<0.05，*P<0.05和**P<0.01）。
7过表达miR-18a后抑制结肠癌细胞的增殖。CCK-8分析表明，与转染NC组比较，过表达miR-18a后显著抑制了HCT116和SW116细胞的增殖，细胞增殖活性降低到近70%（**P<0.01）。而抑制miR-18a则促进HCT116细胞株的增殖(**P<0.01)。
结论：
1ATM基因是miR-18a新的靶基因，但在HCT116细胞中过表达miR-18a升高ATM基因的表达（在电离辐射前和电离辐射后）。这样现象可能是miR-18a对ATM基因3’UTR结合、调控所致，且依赖于不同的细胞背景。
2HCT116细胞中过表达miR-18a可以直接激活基础水平的自噬和增强电离辐射诱导的自噬，致少是部分通过上调自噬调控基因ATM发挥的作用。过表达miR-18a后，通过检测P70S6K蛋白Thr389位点磷酸化受到抑制的情况表明，miR-18a抑制mTORC1的活性，支持miR-18a上调ATM的结论。
3过表达miR-18a增加HCT116细胞对电离辐射的敏感性。
4在结肠癌中miR-18a是发挥抑癌作用的miRNA。
综上所述，本研究揭示miR-18a新的重要的靶基因ATM和miR-18a新的功能，在细胞关键性事件自噬中发挥作用。miR-18a对ATM和自噬的调控作用在肿瘤的发生、发展、治疗以及其他的疾病中会发挥重要作用。因此，miR-18a是结肠癌表观遗传学治疗很好的靶点。
Autophagy is a cellular self-catabolic degradation process whichworks to optimize the bio-energetic cellular microenvironment bydegrading cytoplasmic components such as long-lived proteins anddamaged organelles. Autophagy is active at basal cellular growth levels towork as an endogenous cleaning system, and also can be triggered bydiverse stressful conditions, such as adaptation to starvation, oxidative orgenotoxic stress, and elimination of pathogens. And thus deregulatedautophagy has been observed in various physiological and patho-physiological processes, including aging, cancer and neurodegenerativediseases. The exact role of autophagy in carcinogenesis remains elusive.Autophagy shows dual roles during tumorigenesis as it can behave as atumor suppressor or oncogene depending on the cell context. A similarparadox is exhibited during tumor radio-or chemotherapy therapy,wherein autophagy has been reported to support cancer cell survival and thereby reduce efficacy of the cancer treatment. However, in othercontexts, induction of autophagy has been shown to contribute to cancercell death (also known as programmed cell death type–II) andconsequently enhance therapeutic efficacy of tumor radio-orchemotherapy. Therefore, achieving better molecular understanding ofautophagy and the discovery of specific autophagy modulators suitablefor in vivo use will help to dramatically improve cancer therapy. One ofthe major tumor suppressor genes that have been found recently tomodulate autophagy is ATM (Ataxia telangiectasia mutated). ATM is amulti-functional serine/threonine protein kinase which works to maintaingenomic stability by inducing cell cycle arrest, apoptosis, and DNA repairin response to DNA damage inducing agents particularly ionizingradiation (IR). Newly, ATM has been found to up-regulate autophagyprocess in response to genotoxic and oxidative stimuli. ATM suppressesthe activity of mammalian target of rapamycine complex1(mTORC1)through stimulating AMPK/LKB1/TSC2signaling pathway to ultimatelyinduce autophagy. Therefore, regulating ATM through chemical or genetic methods to modulate autophagy process has become an attractivepoint in cancer research. MicroRNAs are a short (~20–22nucleotideslong) single-stranded RNA molecules, non-coding, novel class of generegulators. They are synthesized from endogenous hairpin-shapedtranscripts (60–110nucleotide RNA precursor structures) in the nucleusthen exported to the cytoplasm. In the cytoplasm the mature microRNAstrand binds to the3'-untranslated region (3'-UTR) of the target mRNAto repress gene expression at the post-transcriptional level. In mammals,it is now predicted that microRNAs control the activity of more than60%of all protein-coding genes. The huge interest in the field of microRNAshas led to the conclusion that microRNAs take part in regulation ofalmost every cellular process known so far like development, growth,apoptosis, and the changes in expression of microRNAs are associatedwith many human disorders especially cancers. MicroRNAs have recentlybeen characterized as modulating the process of autophagy via thetargeting of cardinal autophagy-regulating genes. MiR-30a and miR-376bhave been demonstrated to target and inhibit Beclin-1activity, thereby blocking autophagy. Additionally, miR-101inhibits RAB5A, which actsin the early stages of autophagosome formation.
Objective: Although the field of microRNA-autophagy interrelationshipis still in its infancy, however exploring this filed could help us tounderstand in depth the molecular pathways that control autophagy andoffer future therapeutic perspectives. In our study we were interested todiscover a microRNA that could target ATM efficiently, and then studythe impact of that microRNA on autophagy process (basal and IR-induced autophagy).
Methods:
(1) Bioinformatics analysis was implemented to find a microRNA thatcould target ATM (2) PCR was used to acquire partial3’UTR fragmentand construct luciferase expression plasmids (3) Dual-LuciferaseReporter Assay was used to demonstrate the binding of selectedmicroRNA and ATM target gene (4) X-ray generator was utilized to deliver radiation (5) Western blot was used to analyze ATM proteinexpression level (6) qRT-PCR was used to detect endogenous miRNAexpression (7) GFP-LC3localization assay and LC3-II western blotassay to were used to monitor autophagy process (8) Clonogenic assaywas performed to study the changes in radiosensitivity (9) Cells viabilitywas evaluated by Cell counting Kit-8(10) Student t-test and χ2test wereused to determine statistical significance. P<0.01and P<0.05wereconsidered significant statistically (11) Image J software was used tocalculate the western blot band values.
Results:
1-Chose miR-18a that could bind to the3′-UTR of ATMVia intersecting results from three microRNA target prediction programs(Miranda, Targetscan, and miRDB), miR-18a was found to be a potentcandidate in all three algorithms for targeting ATM. As a putative targetgene, ATM has an extremely conserved single miR-18a target site(position3481-3488of human ATM3’-UTR) in human and other mammalian species, including the chimpanzee, rhesus monkey, mouse,rat, dog and rabbit.
2-miR-18a targets and upregulates ATM gene expression
During luciferase assay, surprisingly, in HCT116colon cancer cells, miR-18a mimic increased the expression of the reporter gene with the ATM3’-UTR tag to almost90%(**P<0.01) as compared to30%in negativecontrol (NC) transfected cells. Almost similar results (*P<0.05) wereobtained when luciferase assay was repeated using lentiviral PCDH-vector expressed miR-18a (PCDH-miR-18a). Western blot results showedthat miR-18a mimic led to1.6folds increase in ATM protein level innon-irradiated and1.7folds increase in4Gy irradiated HCT116cellsrelative to NC transfected cells. Moreover, inhibition of miR-18a led toalmost50%decrease in ATM expression level in irradiated and non-irradiated cells.
3-Endogenous miR-18a expression was up-regulated by ionizingradiation
q-RT-PCR results showed that expression level of endogenous miR-18adramatically increased to more than200folds one hour after exposure ofHCT116to IR. Seven hours after exposure to IR, miR-18a expressionlevel was just more than five folds above the basal level, indicating thatmiR-18a expression changes overtime after exposure to IR. Such resultssuggest that miR-18a could play role in IR-induced cellular events likeautophagy.
4-miR-18a overexpression promotes autophagy:
MiR-18a mimic significantly increased percentage of GFP-LC3puncta-positive cells to15%(**P <0.01) as compared to8%in NC transfectedcells and mock. Further more; the percentage of puncta-positive cellswas further increased up to25%when miR-18a mimic was combined with IR (**P <0.01), relative to cells treated with IR alone (15%).Consistent with GFP-LC3immunofluorescence, miR-18a mimic led tosharp increase in the LC3-II protein expression level in non-irradiated (2folds) and irradiated (3.5folds) HCT116cells as compared to NCtransfected counterparts. P62/SQSTM1is a poly-ubiquitin bindingprotein that was found to bind directly to ATG8/LC3and localize toautophagosomes to ultimately be degraded during autophagy. Therefore,the level of P62reflects the autophagic turnover. In the HCT116cellstransfected with miR-18a mimic, the expression level of theP62/SQSTM1protein was markedly reduced by almost50%in non-irradiated and irradiated cells as compared with the NC transfected cells.Consequently, such findings demonstrate that miR-18a overexpressionenhances the autophagic flux.
5-MiR-18a overexpression inhibits mTORC1activity
ATM has been demonstrated to upregulate autophagy via inhibition ofmTORC1. We hypothesized that miR-18a positively regulated ATM, inhibiting mTORC1and inducing autophagy. To examine whether miR-18a regulated mTORC1, we measured P70S6K phosphorylation atThr389as a typical readout of mTORC1activity by western blotting.MiR-18a mimic markedly decreased the phosphorylation of P70S6K atThr389in non-irradiated and irradiated HCT116cells (which indicatedmTORC1activity inhibition) as compared NC-transfected cells.
6-miR-18a overexpression enhances the radiosensitivity of HCT116cell line
Cologenic survival study showed that miR-18a mimic decreased thesurvival fraction of4,6, and8Gy irradiated HCT116cells (*P<0.05,*P<0.05and**P<0.01respectively) compared to NC transfected cells.
7-Ectopic miR-18a overexpression inhibits the growth of colon cancercells
CCK-8assay surprisingly showed that miR-18a mimic decreased the cell viability to almost70%in HCT116and SW116colon cancer cells(**P<0.01) as compared to NC transfected cells. On the other hand,inhibition of miR-18a increased cell viability (**P<0.01) of HCT116cellline.
Conclusions:
1-ATM is a novel target gene for miR-18a, and ectopic miR-18aoverexpression uniquely promotes ATM gene expression in HCT116colon cancer cells (pre and post-IR exposure). Such phenomena could beprobably through the direct impact of miR-18a on ATM3’UTR segment,which could be cell line-dependent phenomena.
2-Ectopic miR-18a overexpression results in strong induction of basaland IR-induced autophagy in HCT116cells, probably and at leastpartially through regulation of the expression of the known autophagyactivator ATM. This could be partially supported by finding that miR-18a overexpression could suppress mTORC1activity in HCT116cells, as indicated by decreased phosphorylation of P70S6K at Thr389in miR-18amimic transfected cells.
3-Exogenous overexpression of miR-18a enhances the radiationsensitivity of HCT116cells.
4-MiR-18a is a novel tumor suppressor microRNA in colon cancer. MiR-18a belongs to oncogenic miR-17-92cluster which encodes sixmicroRNAs (miR-17, miR-18a, miR-19a, miR-20a, miR-19b-1, and miR-92-1. All other members of this cluster have been previously reported toenhance colon cancer growth especially miR-92. This suggests that miR-18a opposes the oncogenic effect of miR-17-92cluster in colon cancer.In summary, results of the present study pertaining to the role of miR-18ain regulating ATM gene expression and autophagy process in coloncancer cells revealed a novel function for miR-18a in a critical cellularevent and on a crucial gene with significant impacts in cancerdevelopment, progression, treatment and in other diseases. Therefore,miR-18a is a good candidate for novel epigenetic colon cancer therapy.
引文
[1] DUNN W A, JR. Autophagy and related mechanisms of lysosome-mediated protein degradation [J]. Trends in cell biology,1994,4(4):139-43.
[2] MIZUSHIMA N. Autophagy: process and function [J]. Genes&development,2007,21(22):2861-73.
[3] SAHU R, KAUSHIK S, CLEMENT C C, et al. Microautophagy ofcytosolic proteins by late endosomes [J]. Developmental cell,2011,20(1):131-9.
[4] LI W, YANG Q, MAO Z. Chaperone-mediated autophagy:machinery, regulation and biological consequences [J]. Cellular andmolecular life sciences: CMLS,2011,68(5):749-63.
[5] MIZUSHIMA N, LEVINE B, CUERVO A M, et al. Autophagyfights disease through cellular self-digestion [J]. Nature,2008,451(7182):1069-75.
[6] CHEN Y, KLIONSKY D J. The regulation of autophagy-unanswered questions [J]. Journal of cell science,2011,124(Pt2):161-70.
[7] LEVINE B, KROEMER G. Autophagy in the pathogenesis ofdisease [J]. Cell,2008,132(1):27-42.
[8] SHINTANI T, KLIONSKY D J. Autophagy in health and disease:a double-edged sword [J]. Science,2004,306(5698):990-5.
[9] GONZALEZ C D, LEE M S, MARCHETTI P, et al. The emergingrole of autophagy in the pathophysiology of diabetes mellitus [J].Autophagy,2011,7(1):2-11.
[10] MATHEW R, KARANTZA-WADSWORTH V, WHITE E. Roleof autophagy in cancer [J]. Nature reviews Cancer,2007,7(12):961-7.
[11] CUERVO A M. Autophagy: in sickness and in health [J]. Trends incell biology,2004,14(2):70-7.
[12] EDINGER A L, THOMPSON C B. Defective autophagy leads tocancer [J]. Cancer cell,2003,4(6):422-4.
[13] CORNILLON S, FOA C, DAVOUST J, et al. Programmed celldeath in Dictyostelium [J]. Journal of cell science,1994,107(Pt10)(2691-704.
[14] HALL D H, GU G, GARCIA-ANOVEROS J, et al.Neuropathology of degenerative cell death in Caenorhabditis elegans [J].The Journal of neuroscience: the official journal of the Society forNeuroscience,1997,17(3):1033-45.
[15] SHEN H M, CODOGNO P. Autophagic cell death: Loch Nessmonster or endangered species?[J]. Autophagy,2011,7(5):457-65.
[16] LEVINE B, YUAN J. Autophagy in cell death: an innocent convict?[J]. The Journal of clinical investigation,2005,115(10):2679-88.
[17] BURSCH W. The autophagosomal-lysosomal compartment inprogrammed cell death [J]. Cell death and differentiation,2001,8(6):569-81.
[18] CLARKE P G. Developmental cell death: morphological diversityand multiple mechanisms [J]. Anatomy and embryology,1990,181(3):195-213.
[19] LOCKSHIN R A, ZAKERI Z. Apoptosis, autophagy, and more [J].The international journal of biochemistry&cell biology,2004,36(12):2405-19.
[20] PATTINGRE S, TASSA A, QU X, et al. Bcl-2antiapoptoticproteins inhibit Beclin1-dependent autophagy [J]. Cell,2005,122(6):927-39.
[21] SCOTT R C, JUHASZ G, NEUFELD T P. Direct induction ofautophagy by Atg1inhibits cell growth and induces apoptotic cell death[J]. Current biology: CB,2007,17(1):1-11.
[22] BERRY D L, BAEHRECKE E H. Growth arrest and autophagy arerequired for salivary gland cell degradation in Drosophila [J]. Cell,2007,131(6):1137-48.
[23] XU Y, KIM S O, LI Y, et al. Autophagy contributes to caspase-independent macrophage cell death [J]. The Journal of biologicalchemistry,2006,281(28):19179-87.
[24] MAIURI M C, ZALCKVAR E, KIMCHI A, et al. Self-eating andself-killing: crosstalk between autophagy and apoptosis [J]. Naturereviews Molecular cell biology,2007,8(9):741-52.
[25] KROEMER G, LEVINE B. Autophagic cell death: the story of amisnomer [J]. Nature reviews Molecular cell biology,2008,9(12):1004-10.
[26] YANG D S, KUMAR A, STAVRIDES P, et al. Neuronal apoptosisand autophagy cross talk in aging PS/APP mice, a model of Alzheimer'sdisease [J]. The American journal of pathology,2008,173(3):665-81.
[27] HARA T, NAKAMURA K, MATSUI M, et al. Suppression ofbasal autophagy in neural cells causes neurodegenerative disease in mice[J]. Nature,2006,441(7095):885-9.
[28] YANG Z J, CHEE C E, HUANG S, et al. The role of autophagy incancer: therapeutic implications [J]. Molecular cancer therapeutics,2011,10(9):1533-41.
[29] QU X, YU J, BHAGAT G, et al. Promotion of tumorigenesis byheterozygous disruption of the beclin1autophagy gene [J]. The Journalof clinical investigation,2003,112(12):1809-20.
[30] FURUYA N, YU J, BYFIELD M, et al. The evolutionarilyconserved domain of Beclin1is required for Vps34binding, autophagyand tumor suppressor function [J]. Autophagy,2005,1(1):46-52.
[31] AITA V M, LIANG X H, MURTY V V, et al. Cloning andgenomic organization of beclin1, a candidate tumor suppressor gene onchromosome17q21[J]. Genomics,1999,59(1):59-65.
[32] MIRACCO C, COSCI E, OLIVERI G, et al. Protein and mRNAexpression of autophagy gene Beclin1in human brain tumours [J].International journal of oncology,2007,30(2):429-36.
[33] SRIDHAR S, BOTBOL Y, MACIAN F, et al. Autophagy anddisease: always two sides to a problem [J]. The Journal of pathology,2012,226(2):255-73.
[34] KONDO Y, KANZAWA T, SAWAYA R, et al. The role ofautophagy in cancer development and response to therapy [J]. Naturereviews Cancer,2005,5(9):726-34.
[35] YANG S, WANG X, CONTINO G, et al. Pancreatic cancersrequire autophagy for tumor growth [J]. Genes&development,2011,25(7):717-29.
[36] GUO J Y, CHEN H Y, MATHEW R, et al. Activated Ras requiresautophagy to maintain oxidative metabolism and tumorigenesis [J]. Genes&development,2011,25(5):460-70.
[37] AREDIA F, GUAMáN ORTIZ L M, GIANSANTI V, et al.Autophagy and Cancer [J]. Cells,2012,1(3):520-34.
[38] FUJITA N, YOSHIMORI T. Ubiquitination-mediated autophagyagainst invading bacteria [J]. Current opinion in cell biology,2011,23(4):492-7.
[39] ESPERT L, CODOGNO P, BIARD-PIECHACZYK M.Involvement of autophagy in viral infections: antiviral function andsubversion by viruses [J]. J Mol Med (Berl),2007,85(8):811-23.
[40] KUDCHODKAR S B, LEVINE B. Viruses and autophagy [J].Reviews in medical virology,2009,19(6):359-78.
[41] MARINO G, MADEO F, KROEMER G. Autophagy for tissuehomeostasis and neuroprotection [J]. Current opinion in cell biology,2011,23(2):198-206.
[42] RAVIKUMAR B, SARKAR S, DAVIES J E, et al. Regulation ofmammalian autophagy in physiology and pathophysiology [J].Physiological reviews,2010,90(4):1383-435.
[43] NARENDRA D, TANAKA A, SUEN D F, et al. Parkin-inducedmitophagy in the pathogenesis of Parkinson disease [J]. Autophagy,2009,5(5):706-8.
[44] YU W H, CUERVO A M, KUMAR A, et al. Macroautophagy--anovel Beta-amyloid peptide-generating pathway activated in Alzheimer'sdisease [J]. The Journal of cell biology,2005,171(1):87-98.
[45] JIA G, CHENG G, GANGAHAR D M, et al. Insulin-like growthfactor-1and TNF-alpha regulate autophagy through c-jun N-terminalkinase and Akt pathways in human atherosclerotic vascular smooth cells[J]. Immunology and cell biology,2006,84(5):448-54.
[46] MARTINET W, KNAAPEN M W, KOCKX M M, et al.Autophagy in cardiovascular disease [J]. Trends in molecular medicine,2007,13(11):482-91.
[47] YANG Z, KLIONSKY D J. An overview of the molecularmechanism of autophagy [J]. Current topics in microbiology andimmunology,2009,335(1-32.
[48] XIE Z, KLIONSKY D J. Autophagosome formation: coremachinery and adaptations [J]. Nature cell biology,2007,9(10):1102-9.
[49] JUNG C H, JUN C B, RO S H, et al. ULK-Atg13-FIP200complexes mediate mTOR signaling to the autophagy machinery [J].Molecular biology of the cell,2009,20(7):1992-2003.
[50] KAMADA Y, FUNAKOSHI T, SHINTANI T, et al. Tor-mediatedinduction of autophagy via an Apg1protein kinase complex [J]. TheJournal of cell biology,2000,150(6):1507-13.
[51] HOSOKAWA N, HARA T, KAIZUKA T, et al. Nutrient-dependent mTORC1association with the ULK1-Atg13-FIP200complexrequired for autophagy [J]. Molecular biology of the cell,2009,20(7):1981-91.
[52] MERCER C A, KALIAPPAN A, DENNIS P B. A novel, humanAtg13binding protein, Atg101, interacts with ULK1and is essential formacroautophagy [J]. Autophagy,2009,5(5):649-62.
[53] KLIONSKY D J, ABELIOVICH H, AGOSTINIS P, et al.Guidelines for the use and interpretation of assays for monitoringautophagy in higher eukaryotes [J]. Autophagy,2008,4(2):151-75.
[54] JUNG C H, SEO M, OTTO N M, et al. ULK1inhibits the kinaseactivity of mTORC1and cell proliferation [J]. Autophagy,2011,7(10):1212-21.
[55] MIZUSHIMA N, NODA T, YOSHIMORI T, et al. A proteinconjugation system essential for autophagy [J]. Nature,1998,395(6700):395-8.
[56] MIZUSHIMA N, KUMA A, KOBAYASHI Y, et al. MouseApg16L, a novel WD-repeat protein, targets to the autophagic isolationmembrane with the Apg12-Apg5conjugate [J]. Journal of cell science,2003,116(Pt9):1679-88.
[57] KUMA A, MIZUSHIMA N, ISHIHARA N, et al. Formation of theapproximately350-kDa Apg12-Apg5.Apg16multimeric complex,mediated by Apg16oligomerization, is essential for autophagy in yeast[J]. The Journal of biological chemistry,2002,277(21):18619-25.
[58] KIRISAKO T, BABA M, ISHIHARA N, et al. Formation processof autophagosome is traced with Apg8/Aut7p in yeast [J]. The Journal ofcell biology,1999,147(2):435-46.
[59] KIRISAKO T, ICHIMURA Y, OKADA H, et al. The reversiblemodification regulates the membrane-binding state of Apg8/Aut7essential for autophagy and the cytoplasm to vacuole targeting pathway[J]. The Journal of cell biology,2000,151(2):263-76.
[60] ICHIMURA Y, KIRISAKO T, TAKAO T, et al. A ubiquitin-likesystem mediates protein lipidation [J]. Nature,2000,408(6811):488-92.
[61] ICHIMURA Y, IMAMURA Y, EMOTO K, et al. In vivo and invitro reconstitution of Atg8conjugation essential for autophagy [J]. TheJournal of biological chemistry,2004,279(39):40584-92.
[62] FUJITA N, ITOH T, OMORI H, et al. The Atg16L complexspecifies the site of LC3lipidation for membrane biogenesis in autophagy[J]. Molecular biology of the cell,2008,19(5):2092-100.
[63] HANADA T, NODA N N, SATOMI Y, et al. The Atg12-Atg5conjugate has a novel E3-like activity for protein lipidation in autophagy[J]. The Journal of biological chemistry,2007,282(52):37298-302.
[64] SOU Y S, WAGURI S, IWATA J, et al. The Atg8conjugationsystem is indispensable for proper development of autophagic isolationmembranes in mice [J]. Molecular biology of the cell,2008,19(11):4762-75.
[65] SEGLEN P O, GORDON P B.3-Methyladenine: specific inhibitorof autophagic/lysosomal protein degradation in isolated rat hepatocytes[J]. Proceedings of the National Academy of Sciences of the UnitedStates of America,1982,79(6):1889-92.
[66] PETIOT A, OGIER-DENIS E, BLOMMAART E F, et al. Distinctclasses of phosphatidylinositol3'-kinases are involved in signalingpathways that control macroautophagy in HT-29cells [J]. The Journal ofbiological chemistry,2000,275(2):992-8.
[67] ITAKURA E, KISHI C, INOUE K, et al. Beclin1forms twodistinct phosphatidylinositol3-kinase complexes with mammalian Atg14and UVRAG [J]. Molecular biology of the cell,2008,19(12):5360-72.
[68] SUN Q, FAN W, CHEN K, et al. Identification of Barkor as amammalian autophagy-specific factor for Beclin1and class IIIphosphatidylinositol3-kinase [J]. Proceedings of the National Academyof Sciences of the United States of America,2008,105(49):19211-6.
[69] LIANG C, FENG P, KU B, et al. Autophagic and tumoursuppressor activity of a novel Beclin1-binding protein UVRAG [J].Nature cell biology,2006,8(7):688-99.
[70] MATSUNAGA K, SAITOH T, TABATA K, et al. Two Beclin1-binding proteins, Atg14L and Rubicon, reciprocally regulate autophagy atdifferent stages [J]. Nature cell biology,2009,11(4):385-96.
[71] ZHONG Y, WANG Q J, LI X, et al. Distinct regulation ofautophagic activity by Atg14L and Rubicon associated with Beclin1-phosphatidylinositol-3-kinase complex [J]. Nature cell biology,2009,11(4):468-76.
[72] BULLER C L, LOBERG R D, FAN M H, et al. A GSK-3/TSC2/mTOR pathway regulates glucose uptake and GLUT1glucosetransporter expression [J]. American journal of physiology Cellphysiology,2008,295(3): C836-43.
[73] TAKAHASHI Y, COPPOLA D, MATSUSHITA N, et al. Bif-1interacts with Beclin1through UVRAG and regulates autophagy andtumorigenesis [J]. Nature cell biology,2007,9(10):1142-51.
[74] TAKAHASHI Y, MEYERKORD C L, WANG H G. Bif-1/endophilin B1: a candidate for crescent driving force in autophagy [J].Cell death and differentiation,2009,16(7):947-55.
[75] LIANG C, LEE J S, INN K S, et al. Beclin1-binding UVRAGtargets the class C Vps complex to coordinate autophagosome maturationand endocytic trafficking [J]. Nature cell biology,2008,10(7):776-87.
[76] FIMIA G M, STOYKOVA A, ROMAGNOLI A, et al. Ambra1regulates autophagy and development of the nervous system [J]. Nature,2007,447(7148):1121-5.
[77] YOUNG A R, CHAN E Y, HU X W, et al. Starvation and ULK1-dependent cycling of mammalian Atg9between the TGN and endosomes[J]. Journal of cell science,2006,119(Pt18):3888-900.
[78] REGGIORI F, TUCKER K A, STROMHAUG P E, et al. TheAtg1-Atg13complex regulates Atg9and Atg23retrieval transport fromthe pre-autophagosomal structure [J]. Developmental cell,2004,6(1):79-90.
[79] ROPOLO A, GRASSO D, PARDO R, et al. The pancreatitis-induced vacuole membrane protein1triggers autophagy in mammaliancells [J]. The Journal of biological chemistry,2007,282(51):37124-33.
[80] NOWAK J, ARCHANGE C, TARDIVEL-LACOMBE J, et al. TheTP53INP2protein is required for autophagy in mammalian cells [J].Molecular biology of the cell,2009,20(3):870-81.
[81] WANG X, PROUD C G. mTORC1signaling: what we still don'tknow [J]. Journal of molecular cell biology,2011,3(4):206-20.
[82] WATANABE R, WEI L, HUANG J. mTOR signaling, function,novel inhibitors, and therapeutic targets [J]. Journal of nuclear medicine:official publication, Society of Nuclear Medicine,2011,52(4):497-500.
[83] SENGUPTA S, PETERSON T R, SABATINI D M. Regulation ofthe mTOR complex1pathway by nutrients, growth factors, and stress [J].Molecular cell,2010,40(2):310-22.
[84] POPULO H, LOPES J M, SOARES P. The mTOR SignallingPathway in Human Cancer [J]. International journal of molecular sciences,2012,13(2):1886-918.
[85] CODOGNO P, MEIJER A J. Autophagy and signaling: their rolein cell survival and cell death [J]. Cell death and differentiation,2005,12Suppl2(1509-18.
[86] SARBASSOV D D, ALI S M, SENGUPTA S, et al. Prolongedrapamycin treatment inhibits mTORC2assembly and Akt/PKB [J].Molecular cell,2006,22(2):159-68.
[87] GUERTIN D A, SABATINI D M. Defining the role of mTOR incancer [J]. Cancer cell,2007,12(1):9-22.
[88] MAGNUSON B, EKIM B, FINGAR D C. Regulation and functionof ribosomal protein S6kinase (S6K) within mTOR signalling networks[J]. The Biochemical journal,2012,441(1):1-21.
[89] BROWN E J, BEAL P A, KEITH C T, et al. Control of p70s6kinase by kinase activity of FRAP in vivo [J]. Nature,1995,377(6548):441-6.
[90] LAWRENCE J C, JR., ABRAHAM R T. PHAS/4E-BPs asregulators of mRNA translation and cell proliferation [J]. Trends inbiochemical sciences,1997,22(9):345-9.
[91] ARICO S, PETIOT A, BAUVY C, et al. The tumor suppressorPTEN positively regulates macroautophagy by inhibiting thephosphatidylinositol3-kinase/protein kinase B pathway [J]. The Journalof biological chemistry,2001,276(38):35243-6.
[92] INOKI K, LI Y, ZHU T, et al. TSC2is phosphorylated andinhibited by Akt and suppresses mTOR signalling [J]. Nature cell biology,2002,4(9):648-57.
[93] MA L, CHEN Z, ERDJUMENT-BROMAGE H, et al.Phosphorylation and functional inactivation of TSC2by Erk implicationsfor tuberous sclerosis and cancer pathogenesis [J]. Cell,2005,121(2):179-93.
[94] HE C, KLIONSKY D J. Regulation mechanisms and signalingpathways of autophagy [J]. Annual review of genetics,2009,43(67-93.
[95] FURUTA S, HIDAKA E, OGATA A, et al. Ras is involved in thenegative control of autophagy through the class I PI3-kinase [J].Oncogene,2004,23(22):3898-904.
[96] PATTINGRE S, BAUVY C, CODOGNO P. Amino acids interferewith the ERK1/2-dependent control of macroautophagy by controlling theactivation of Raf-1in human colon cancer HT-29cells [J]. The Journal ofbiological chemistry,2003,278(19):16667-74.
[97] SARBASSOV D D, GUERTIN D A, ALI S M, et al.Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex[J]. Science,2005,307(5712):1098-101.
[98] MAMMUCARI C, MILAN G, ROMANELLO V, et al. FoxO3controls autophagy in skeletal muscle in vivo [J]. Cell metabolism,2007,6(6):458-71.
[99] GWINN D M, SHACKELFORD D B, EGAN D F, et al. AMPKphosphorylation of raptor mediates a metabolic checkpoint [J]. Molecularcell,2008,30(2):214-26.
[100] LIANG J, SHAO S H, XU Z X, et al. The energy sensing LKB1-AMPK pathway regulates p27(kip1) phosphorylation mediating thedecision to enter autophagy or apoptosis [J]. Nature cell biology,2007,9(2):218-24.
[101] HOYER-HANSEN M, BASTHOLM L, SZYNIAROWSKI P, et al.Control of macroautophagy by calcium, calmodulin-dependent kinasekinase-beta, and Bcl-2[J]. Molecular cell,2007,25(2):193-205.
[102] HERRERO-MARTIN G, HOYER-HANSEN M, GARCIA-GARCIA C, et al. TAK1activates AMPK-dependent cytoprotectiveautophagy in TRAIL-treated epithelial cells [J]. The EMBO journal,2009,28(6):677-85.
[103] PAPANDREOU I, LIM A L, LADEROUTE K, et al. Hypoxiasignals autophagy in tumor cells via AMPK activity, independent of HIF-1, BNIP3, and BNIP3L [J]. Cell death and differentiation,2008,15(10):1572-81.
[104] LEVINE B, ABRAMS J. p53: The Janus of autophagy?[J]. Naturecell biology,2008,10(6):637-9.
[105] FENG Z, ZHANG H, LEVINE A J, et al. The coordinateregulation of the p53and mTOR pathways in cells [J]. Proceedings of theNational Academy of Sciences of the United States of America,2005,102(23):8204-9.
[106] CRIGHTON D, WILKINSON S, O'PREY J, et al. DRAM, a p53-induced modulator of autophagy, is critical for apoptosis [J]. Cell,2006,126(1):121-34.
[107] TASDEMIR E, MAIURI M C, GALLUZZI L, et al. Regulation ofautophagy by cytoplasmic p53[J]. Nature cell biology,2008,10(6):676-87.
[108] MORSELLI E, TASDEMIR E, MAIURI M C, et al. Mutant p53protein localized in the cytoplasm inhibits autophagy [J]. Cell Cycle,2008,7(19):3056-61.
[109] SUI X, JIN L, HUANG X, et al. p53signaling and autophagy incancer: a revolutionary strategy could be developed for cancer treatment[J]. Autophagy,2011,7(6):565-71.
[110] LEVINE B, SINHA S, KROEMER G. Bcl-2family members: dualregulators of apoptosis and autophagy [J]. Autophagy,2008,4(5):600-6.
[111] MAIURI M C, LE TOUMELIN G, CRIOLLO A, et al. Functionaland physical interaction between Bcl-X(L) and a BH3-like domain inBeclin-1[J]. The EMBO journal,2007,26(10):2527-39.
[112] WEI Y, PATTINGRE S, SINHA S, et al. JNK1-mediatedphosphorylation of Bcl-2regulates starvation-induced autophagy [J].Molecular cell,2008,30(6):678-88.
[113] ZALCKVAR E, BERISSI H, MIZRACHY L, et al. DAP-kinase-mediated phosphorylation on the BH3domain of beclin1promotesdissociation of beclin1from Bcl-XL and induction of autophagy [J].EMBO reports,2009,10(3):285-92.
[114] KASTAN M B, LIM D S. The many substrates and functions ofATM [J]. Nature reviews Molecular cell biology,2000,1(3):179-86.
[115] LAVIN M F, SHILOH Y. The genetic defect in ataxia-telangiectasia [J]. Annual review of immunology,1997,15(177-202.
[116] SAVITSKY K, SFEZ S, TAGLE D A, et al. The completesequence of the coding region of the ATM gene reveals similarity to cellcycle regulators in different species [J]. Human molecular genetics,1995,4(11):2025-32.
[117] GATTI R A, BERKEL I, BODER E, et al. Localization of anataxia-telangiectasia gene to chromosome11q22-23[J]. Nature,1988,336(6199):577-80.
[118] ABRAHAM R T. PI3-kinase related kinases:'big' players instress-induced signaling pathways [J]. DNA repair,2004,3(8-9):883-7.
[119] BAKKENIST C J, KASTAN M B. DNA damage activates ATMthrough intermolecular autophosphorylation and dimer dissociation [J].Nature,2003,421(6922):499-506.
[120] ANDEGEKO Y, MOYAL L, MITTELMAN L, et al. Nuclearretention of ATM at sites of DNA double strand breaks [J]. The Journalof biological chemistry,2001,276(41):38224-30.
[121] D'AMOURS D, JACKSON S P. The Mre11complex: at thecrossroads of dna repair and checkpoint signalling [J]. Nature reviewsMolecular cell biology,2002,3(5):317-27.
[122] UZIEL T, LERENTHAL Y, MOYAL L, et al. Requirement of theMRN complex for ATM activation by DNA damage [J]. The EMBOjournal,2003,22(20):5612-21.
[123] LAVIN M F. The Mre11complex and ATM: a two-way functionalinteraction in recognising and signaling DNA double strand breaks [J].DNA repair,2004,3(11):1515-20.
[124] LEE J H, PAULL T T. ATM activation by DNA double-strandbreaks through the Mre11-Rad50-Nbs1complex [J]. Science,2005,308(5721):551-4.
[125] KITAGAWA R, BAKKENIST C J, MCKINNON P J, et al.Phosphorylation of SMC1is a critical downstream event in the ATM-NBS1-BRCA1pathway [J]. Genes&development,2004,18(12):1423-38.
[126] PETRINI J H, STRACKER T H. The cellular response to DNAdouble-strand breaks: defining the sensors and mediators [J]. Trends incell biology,2003,13(9):458-62.
[127] SHILOH Y. ATM and related protein kinases: safeguardinggenome integrity [J]. Nature reviews Cancer,2003,3(3):155-68.
[128] POLO S E, JACKSON S P. Dynamics of DNA damage responseproteins at DNA breaks: a focus on protein modifications [J]. Genes&development,2011,25(5):409-33.
[129] KASTAN M B, ONYEKWERE O, SIDRANSKY D, et al.Participation of p53protein in the cellular response to DNA damage [J].Cancer research,1991,51(23Pt1):6304-11.
[130] CANMAN C E, LIM D S, CIMPRICH K A, et al. Activation of theATM kinase by ionizing radiation and phosphorylation of p53[J].Science,1998,281(5383):1677-9.
[131] LIM D S, KIM S T, XU B, et al. ATM phosphorylates p95/nbs1inan S-phase checkpoint pathway [J]. Nature,2000,404(6778):613-7.
[132] XU B, O'DONNELL A H, KIM S T, et al. Phosphorylation ofserine1387in Brca1is specifically required for the Atm-mediated S-phase checkpoint after ionizing irradiation [J]. Cancer research,2002,62(16):4588-91.
[133] KASTAN M B, BARTEK J. Cell-cycle checkpoints and cancer [J].Nature,2004,432(7015):316-23.
[134] LUKAS J, LUKAS C, BARTEK J. Mammalian cell cyclecheckpoints: signalling pathways and their organization in space and time[J]. DNA repair,2004,3(8-9):997-1007.
[135] BAO S, TIBBETTS R S, BRUMBAUGH K M, et al. ATR/ATM-mediated phosphorylation of human Rad17is required for genotoxicstress responses [J]. Nature,2001,411(6840):969-74.
[136] SAPKOTA G P, DEAK M, KIELOCH A, et al. Ionizing radiationinduces ataxia telangiectasia mutated kinase (ATM)-mediatedphosphorylation of LKB1/STK11at Thr-366[J]. The Biochemicaljournal,2002,368(Pt2):507-16.
[137] ALEXANDER A, WALKER C L. The role of LKB1and AMPKin cellular responses to stress and damage [J]. FEBS letters,2011,585(7):952-7.
[138] ALEXANDER A, CAI S L, KIM J, et al. ATM signals to TSC2inthe cytoplasm to regulate mTORC1in response to ROS [J]. Proceedingsof the National Academy of Sciences of the United States of America,2010,107(9):4153-8.
[139] MENENDEZ J A, CUFI S, OLIVERAS-FERRAROS C, et al.Metformin and the ATM DNA damage response (DDR): accelerating theonset of stress-induced senescence to boost protection against cancer [J].Aging,2011,3(11):1063-77.
[140] BUDANOV A V, KARIN M. p53target genes sestrin1andsestrin2connect genotoxic stress and mTOR signaling [J]. Cell,2008,134(3):451-60.
[141] DUAN X, PONOMAREVA L, VEERANKI S, et al. IFI16induction by glucose restriction in human fibroblasts contributes toautophagy through activation of the ATM/AMPK/p53pathway [J]. PloSone,2011,6(5): e19532.
[142] ZHOU W J, DENG R, ZHANG X Y, et al. G-quadruplex ligandSYUIQ-5induces autophagy by telomere damage and TRF2delocalization in cancer cells [J]. Molecular cancer therapeutics,2009,8(12):3203-13.
[143] CHEN L H, LOONG C C, SU T L, et al. Autophagy inhibitionenhances apoptosis triggered by BO-1051, an N-mustard derivative, andinvolves the ATM signaling pathway [J]. Biochemical pharmacology,2011,81(5):594-605.
[144] SINGH K, MATSUYAMA S, DRAZBA J A, et al. Autophagy-dependent senescence in response to DNA damage and chronic apoptoticstress [J]. Autophagy,2012,8(2):236-51.
[145] BRICHKINA A, BULAVIN D V. WIP-ing out atherosclerosiswith autophagy [J]. Autophagy,2012,8(10):1545-7.
[146] LE GUEZENNEC X, BRICHKINA A, HUANG Y F, et al. Wip1-dependent regulation of autophagy, obesity, and atherosclerosis [J]. Cellmetabolism,2012,16(1):68-80.
[147] ZHOU K, BELLENGUEZ C, SPENCER C C, et al. Commonvariants near ATM are associated with glycemic response to metformin intype2diabetes [J]. Nature genetics,2011,43(2):117-20.
[148] LEE R, FEINBAUM R, AMBROS V. A short history of a shortRNA [J]. Cell,2004,116(2Suppl): S89-92,1p following S6.
[149] RUVKUN G, WIGHTMAN B, HA I. The20years it took torecognize the importance of tiny RNAs [J]. Cell,2004,116(2Suppl):S93-6,2p following S6.
[150] REINHART B J, SLACK F J, BASSON M, et al. The21-nucleotide let-7RNA regulates developmental timing in Caenorhabditiselegans [J]. Nature,2000,403(6772):901-6.
[151] GRIFFITHS-JONES S. The microRNA Registry [J]. Nucleic acidsresearch,2004,32(Database issue): D109-11.
[152] FRIEDMAN R C, FARH K K, BURGE C B, et al. Mostmammalian mRNAs are conserved targets of microRNAs [J]. Genomeresearch,2009,19(1):92-105.
[153] SELBACH M, SCHWANHAUSSER B, THIERFELDER N, et al.Widespread changes in protein synthesis induced by microRNAs [J].Nature,2008,455(7209):58-63.
[154] SAINI H K, GRIFFITHS-JONES S, ENRIGHT A J. Genomicanalysis of human microRNA transcripts [J]. Proceedings of the NationalAcademy of Sciences of the United States of America,2007,104(45):17719-24.
[155] RODRIGUEZ A, GRIFFITHS-JONES S, ASHURST J L, et al.Identification of mammalian microRNA host genes and transcriptionunits [J]. Genome research,2004,14(10A):1902-10.
[156] KIM V N. MicroRNA biogenesis: coordinated cropping and dicing[J]. Nature reviews Molecular cell biology,2005,6(5):376-85.
[157] LEE Y, KIM M, HAN J, et al. MicroRNA genes are transcribed byRNA polymerase II [J]. The EMBO journal,2004,23(20):4051-60.
[158] BORCHERT G M, LANIER W, DAVIDSON B L. RNApolymerase III transcribes human microRNAs [J]. Nature structural&molecular biology,2006,13(12):1097-101.
[159] DENLI A M, TOPS B B, PLASTERK R H, et al. Processing ofprimary microRNAs by the Microprocessor complex [J]. Nature,2004,432(7014):231-5.
[160] HAN J, LEE Y, YEOM K H, et al. Molecular basis for therecognition of primary microRNAs by the Drosha-DGCR8complex [J].Cell,2006,125(5):887-901.
[161] LUND E, GUTTINGER S, CALADO A, et al. Nuclear export ofmicroRNA precursors [J]. Science,2004,303(5654):95-8.
[162] BOHNSACK M T, CZAPLINSKI K, GORLICH D. Exportin5is aRanGTP-dependent dsRNA-binding protein that mediates nuclear exportof pre-miRNAs [J]. RNA,2004,10(2):185-91.
[163] HUTVAGNER G, MCLACHLAN J, PASQUINELLI A E, et al. Acellular function for the RNA-interference enzyme Dicer in thematuration of the let-7small temporal RNA [J]. Science,2001,293(5531):834-8.
[164] GREGORY R I, CHENDRIMADA T P, COOCH N, et al. HumanRISC couples microRNA biogenesis and posttranscriptional genesilencing [J]. Cell,2005,123(4):631-40.
[165] MACRAE I J, DOUDNA J A. Ribonuclease revisited: structuralinsights into ribonuclease III family enzymes [J]. Current opinion instructural biology,2007,17(1):138-45.
[166] MACRAE I J, ZHOU K, DOUDNA J A. Structural determinantsof RNA recognition and cleavage by Dicer [J]. Nature structural&molecular biology,2007,14(10):934-40.
[167] MACRAE I J, ZHOU K, LI F, et al. Structural basis for double-stranded RNA processing by Dicer [J]. Science,2006,311(5758):195-8.
[168] CHENDRIMADA T P, GREGORY R I, KUMARASWAMY E, etal. TRBP recruits the Dicer complex to Ago2for microRNA processingand gene silencing [J]. Nature,2005,436(7051):740-4.
[169] LEE Y, HUR I, PARK S Y, et al. The role of PACT in the RNAsilencing pathway [J]. The EMBO journal,2006,25(3):522-32.
[170] HUTVAGNER G, SIMARD M J. Argonaute proteins: key playersin RNA silencing [J]. Nature reviews Molecular cell biology,2008,9(1):22-32.
[171] SETO A G, KINGSTON R E, LAU N C. The coming of age forPiwi proteins [J]. Molecular cell,2007,26(5):603-9.
[172] HUTVAGNER G. Small RNA asymmetry in RNAi: function inRISC assembly and gene regulation [J]. FEBS letters,2005,579(26):5850-7.
[173] RO S, PARK C, YOUNG D, et al. Tissue-dependent pairedexpression of miRNAs [J]. Nucleic acids research,2007,35(17):5944-53.
[174] BASKERVILLE S, BARTEL D P. Microarray profiling ofmicroRNAs reveals frequent coexpression with neighboring miRNAs andhost genes [J]. RNA,2005,11(3):241-7.
[175] SONG G, WANG L. MiR-433and miR-127arise fromindependent overlapping primary transcripts encoded by the miR-433-127locus [J]. PloS one,2008,3(10): e3574.
[176] SEMPERE L F, FREEMANTLE S, PITHA-ROWE I, et al.Expression profiling of mammalian microRNAs uncovers a subset ofbrain-expressed microRNAs with possible roles in murine and humanneuronal differentiation [J]. Genome biology,2004,5(3): R13.
[177] GUIL S, CACERES J F. The multifunctional RNA-binding proteinhnRNP A1is required for processing of miR-18a [J]. Nature structural&molecular biology,2007,14(7):591-6.
[178] MEYER N, PENN L Z. Reflecting on25years with MYC [J].Nature reviews Cancer,2008,8(12):976-90.
[179] O'DONNELL K A, WENTZEL E A, ZELLER K I, et al. c-Myc-regulated microRNAs modulate E2F1expression [J]. Nature,2005,435(7043):839-43.
[180] CHANG T C, YU D, LEE Y S, et al. Widespread microRNArepression by Myc contributes to tumorigenesis [J]. Nature genetics,2008,40(1):43-50.
[181] RAVER-SHAPIRA N, MARCIANO E, MEIRI E, et al.Transcriptional activation of miR-34a contributes to p53-mediatedapoptosis [J]. Molecular cell,2007,26(5):731-43.
[182] BARTEL D P. MicroRNAs: genomics, biogenesis, mechanism,and function [J]. Cell,2004,116(2):281-97.
[183] BRENNECKE J, STARK A, RUSSELL R B, et al. Principles ofmicroRNA-target recognition [J]. PLoS biology,2005,3(3): e85.
[184] BRODERSEN P, VOINNET O. Revisiting the principles ofmicroRNA target recognition and mode of action [J]. Nature reviewsMolecular cell biology,2009,10(2):141-8.
[185] MERRICK W C. Cap-dependent and cap-independent translationin eukaryotic systems [J]. Gene,2004,332(1-11.
[186] DERRY M C, YANAGIYA A, MARTINEAU Y, et al. Regulationof poly(A)-binding protein through PABP-interacting proteins [J]. ColdSpring Harbor symposia on quantitative biology,2006,71(537-43.
[187] JACKSON R J. Alternative mechanisms of initiating translation ofmammalian mRNAs [J]. Biochemical Society transactions,2005,33(Pt6):1231-41.
[188] PILLAI R S, BHATTACHARYYA S N, ARTUS C G, et al.Inhibition of translational initiation by Let-7MicroRNA in human cells[J]. Science,2005,309(5740):1573-6.
[189] HUMPHREYS D T, WESTMAN B J, MARTIN D I, et al.MicroRNAs control translation initiation by inhibiting eukaryoticinitiation factor4E/cap and poly(A) tail function [J]. Proceedings of theNational Academy of Sciences of the United States of America,2005,102(47):16961-6.
[190] CHO P F, POULIN F, CHO-PARK Y A, et al. A new paradigm fortranslational control: inhibition via5'-3' mRNA tethering by Bicoid andthe eIF4E cognate4EHP [J]. Cell,2005,121(3):411-23.
[191] RICHTER J D, SONENBERG N. Regulation of cap-dependenttranslation by eIF4E inhibitory proteins [J]. Nature,2005,433(7025):477-80.
[192] KIRIAKIDOU M, TAN G S, LAMPRINAKI S, et al. An mRNAm7G cap binding-like motif within human Ago2represses translation [J].Cell,2007,129(6):1141-51.
[193] WAKIYAMA M, TAKIMOTO K, OHARA O, et al. Let-7microRNA-mediated mRNA deadenylation and translational repressionin a mammalian cell-free system [J]. Genes&development,2007,21(15):1857-62.
[194] WANG B, LOVE T M, CALL M E, et al. Recapitulation of shortRNA-directed translational gene silencing in vitro [J]. Molecular cell,2006,22(4):553-60.
[195] CHENDRIMADA T P, FINN K J, JI X, et al. MicroRNA silencingthrough RISC recruitment of eIF6[J]. Nature,2007,447(7146):823-8.
[196] BASU U, SI K, WARNER J R, et al. The Saccharomycescerevisiae TIF6gene encoding translation initiation factor6is requiredfor60S ribosomal subunit biogenesis [J]. Molecular and cellular biology,2001,21(5):1453-62.
[197] OLSEN P H, AMBROS V. The lin-4regulatory RNA controlsdevelopmental timing in Caenorhabditis elegans by blocking LIN-14protein synthesis after the initiation of translation [J]. Developmentalbiology,1999,216(2):671-80.
[198] SEGGERSON K, TANG L, MOSS E G. Two genetic circuitsrepress the Caenorhabditis elegans heterochronic gene lin-28aftertranslation initiation [J]. Developmental biology,2002,243(2):215-25.
[199] PETERSEN C P, BORDELEAU M E, PELLETIER J, et al. ShortRNAs repress translation after initiation in mammalian cells [J].Molecular cell,2006,21(4):533-42.
[200] NOTTROTT S, SIMARD M J, RICHTER J D. Human let-7amiRNA blocks protein production on actively translating polyribosomes[J]. Nature structural&molecular biology,2006,13(12):1108-14.
[201] WU L, FAN J, BELASCO J G. MicroRNAs direct rapiddeadenylation of mRNA [J]. Proceedings of the National Academy ofSciences of the United States of America,2006,103(11):4034-9.
[202] LIM L P, LAU N C, GARRETT-ENGELE P, et al. Microarrayanalysis shows that some microRNAs downregulate large numbers oftarget mRNAs [J]. Nature,2005,433(7027):769-73.
[203] BAGGA S, BRACHT J, HUNTER S, et al. Regulation by let-7andlin-4miRNAs results in target mRNA degradation [J]. Cell,2005,122(4):553-63.
[204] PARKER R, SONG H. The enzymes and control of eukaryoticmRNA turnover [J]. Nature structural&molecular biology,2004,11(2):121-7.
[205] BEHM-ANSMANT I, REHWINKEL J, DOERKS T, et al. mRNAdegradation by miRNAs and GW182requires both CCR4:NOTdeadenylase and DCP1:DCP2decapping complexes [J]. Genes&development,2006,20(14):1885-98.
[206] GIRALDEZ A J, MISHIMA Y, RIHEL J, et al. Zebrafish MiR-430promotes deadenylation and clearance of maternal mRNAs [J]. Science,2006,312(5770):75-9.
[207] MEISTER G, LANDTHALER M, PATKANIOWSKA A, et al.Human Argonaute2mediates RNA cleavage targeted by miRNAs andsiRNAs [J]. Molecular cell,2004,15(2):185-97.
[208] EULALIO A, BEHM-ANSMANT I, IZAURRALDE E. P bodies:at the crossroads of post-transcriptional pathways [J]. Nature reviewsMolecular cell biology,2007,8(1):9-22.
[209] LIU J, VALENCIA-SANCHEZ M A, HANNON G J, et al.MicroRNA-dependent localization of targeted mRNAs to mammalian P-bodies [J]. Nature cell biology,2005,7(7):719-23.
[210] SEN G L, BLAU H M. Argonaute2/RISC resides in sites ofmammalian mRNA decay known as cytoplasmic bodies [J]. Nature cellbiology,2005,7(6):633-6.
[211] EYSTATHIOY T, CHAN E K, TENENBAUM S A, et al. Aphosphorylated cytoplasmic autoantigen, GW182, associates with aunique population of human mRNAs within novel cytoplasmic speckles[J]. Molecular biology of the cell,2002,13(4):1338-51.
[212] JAKYMIW A, LIAN S, EYSTATHIOY T, et al. Disruption of GWbodies impairs mammalian RNA interference [J]. Nature cell biology,2005,7(12):1267-74.
[213] LIU J, RIVAS F V, WOHLSCHLEGEL J, et al. A role for the P-body component GW182in microRNA function [J]. Nature cell biology,2005,7(12):1261-6.
[214] PAULEY K M, EYSTATHIOY T, JAKYMIW A, et al. Formationof GW bodies is a consequence of microRNA genesis [J]. EMBO reports,2006,7(9):904-10.
[215] CHAN S P, SLACK F J. microRNA-mediated silencing inside P-bodies [J]. RNA biology,2006,3(3):97-100.
[216] VALENCIA-SANCHEZ M A, LIU J, HANNON G J, et al.Control of translation and mRNA degradation by miRNAs and siRNAs[J]. Genes&development,2006,20(5):515-24.
[217] BHATTACHARYYA S N, HABERMACHER R, MARTINE U, etal. Relief of microRNA-mediated translational repression in human cellssubjected to stress [J]. Cell,2006,125(6):1111-24.
[218] MACFARLANE L A, MURPHY P R. MicroRNA: Biogenesis,Function and Role in Cancer [J]. Current genomics,2010,11(7):537-61.
[219] IVEY K N, SRIVASTAVA D. MicroRNAs as regulators ofdifferentiation and cell fate decisions [J]. Cell stem cell,2010,7(1):36-41.
[220] WIENHOLDS E, PLASTERK R H. MicroRNA function in animaldevelopment [J]. FEBS letters,2005,579(26):5911-22.
[221] O'CONNELL R M, RAO D S, CHAUDHURI A A, et al.Physiological and pathological roles for microRNAs in the immunesystem [J]. Nature reviews Immunology,2010,10(2):111-22.
[222] SUAREZ Y, SESSA W C. MicroRNAs as novel regulators ofangiogenesis [J]. Circulation research,2009,104(4):442-54.
[223] WANG Y, LEE C G. MicroRNA and cancer--focus on apoptosis[J]. Journal of cellular and molecular medicine,2009,13(1):12-23.
[224] LI Y, KOWDLEY K V. MicroRNAs in Common Human Diseases[J]. Genomics, proteomics&bioinformatics,2012,10(5):246-53.
[225] LIMA R T, BUSACCA S, ALMEIDA G M, et al. MicroRNAregulation of core apoptosis pathways in cancer [J]. Eur J Cancer,2011,47(2):163-74.
[226] ZHANG B, PAN X, COBB G P, et al. microRNAs as oncogenesand tumor suppressors [J]. Developmental biology,2007,302(1):1-12.
[227] JIANG Q, WANG Y, HAO Y, et al. miR2Disease: a manuallycurated database for microRNA deregulation in human disease [J].Nucleic acids research,2009,37(Database issue): D98-104.
[228] HRASOVEC S, GLAVAC D. MicroRNAs as Novel Biomarkers inColorectal Cancer [J]. Frontiers in genetics,2012,3(180.
[229] HUANG Z, HUANG D, NI S, et al. Plasma microRNAs arepromising novel biomarkers for early detection of colorectal cancer [J].International journal of cancer Journal international du cancer,2010,127(1):118-26.
[230] NG E K, CHONG W W, JIN H, et al. Differential expression ofmicroRNAs in plasma of patients with colorectal cancer: a potentialmarker for colorectal cancer screening [J]. Gut,2009,58(10):1375-81.
[231] AHMED F E, JEFFRIES C D, VOS P W, et al. DiagnosticmicroRNA markers for screening sporadic human colon cancer and activeulcerative colitis in stool and tissue [J]. Cancer genomics&proteomics,2009,6(5):281-95.
[232] SLABY O, SVOBODA M, FABIAN P, et al. Altered expression ofmiR-21, miR-31, miR-143and miR-145is related to clinicopathologicfeatures of colorectal cancer [J]. Oncology,2007,72(5-6):397-402.
[233] SCHETTER A J, LEUNG S Y, SOHN J J, et al. MicroRNAexpression profiles associated with prognosis and therapeutic outcome incolon adenocarcinoma [J]. JAMA: the journal of the American MedicalAssociation,2008,299(4):425-36.
[234] KULDA V, PESTA M, TOPOLCAN O, et al. Relevance of miR-21and miR-143expression in tissue samples of colorectal carcinoma andits liver metastases [J]. Cancer genetics and cytogenetics,2010,200(2):154-60.
[235] IBRAHIM A F, WEIRAUCH U, THOMAS M, et al. MicroRNAreplacement therapy for miR-145and miR-33a is efficacious in a modelof colon carcinoma [J]. Cancer research,2011,71(15):5214-24.
[236] ASLAM M I, PATEL M, SINGH B, et al. MicroRNAmanipulation in colorectal cancer cells: from laboratory to clinicalapplication [J]. Journal of translational medicine,2012,10(128.
[237] WANG P, ZOU F, ZHANG X, et al. microRNA-21negativelyregulates Cdc25A and cell cycle progression in colon cancer cells [J].Cancer research,2009,69(20):8157-65.
[238] WU H, WANG F, HU S, et al. MiR-20a and miR-106b negativelyregulate autophagy induced by leucine deprivation via suppression ofULK1expression in C2C12myoblasts [J]. Cellular signalling,2012,24(11):2179-86.
[239] FU L L, WEN X, BAO J K, et al. MicroRNA-modulatedautophagic signaling networks in cancer [J]. The international journal ofbiochemistry&cell biology,2012,44(5):733-6.
[240] WANG Y X, ZHANG X Y, ZHANG B F, et al. Initial study ofmicroRNA expression profiles of colonic cancer without lymph nodemetastasis [J]. Journal of digestive diseases,2010,11(1):50-4.
[241] DIOSDADO B, VAN DE WIEL M A, TERHAAR SIVE DROSTEJ S, et al. MiR-17-92cluster is associated with13q gain and c-mycexpression during colorectal adenoma to adenocarcinoma progression [J].British journal of cancer,2009,101(4):707-14.
[242] FANG Z M, LEE C S, SARRIS M, et al. Rapid radiation-inductionof ATM protein levels in situ [J]. Pathology,2001,33(1):30-6.
[243] MIZUSHIMA N. Methods for monitoring autophagy using GFP-LC3transgenic mice [J]. Methods in enzymology,2009,452(13-23.
[244] BJORKOY G, LAMARK T, BRECH A, et al. p62/SQSTM1formsprotein aggregates degraded by autophagy and has a protective effect onhuntingtin-induced cell death [J]. The Journal of cell biology,2005,171(4):603-14.
[245] MIZUSHIMA N, YOSHIMORI T, LEVINE B. Methods inmammalian autophagy research [J]. Cell,2010,140(3):313-26.
[246] KHANNA K K, LAVIN M F, JACKSON S P, et al. ATM, acentral controller of cellular responses to DNA damage [J]. Cell deathand differentiation,2001,8(11):1052-65.
[247] DELIA D, FONTANELLA E, FERRARIO C, et al. DNA damage-induced cell-cycle phase regulation of p53and p21waf1in normal andATM-defective cells [J]. Oncogene,2003,22(49):7866-9.
[248] GAUL L, MANDL-WEBER S, BAUMANN P, et al.Bendamustine induces G2cell cycle arrest and apoptosis in myelomacells: the role of ATM-Chk2-Cdc25A and ATM-p53-p21-pathways [J].Journal of cancer research and clinical oncology,2008,134(2):245-53.
[249] HICKSON I, ZHAO Y, RICHARDSON C J, et al. Identificationand characterization of a novel and specific inhibitor of the ataxia-telangiectasia mutated kinase ATM [J]. Cancer research,2004,64(24):9152-9.
[250] GOLDING S E, ROSENBERG E, VALERIE N, et al. ImprovedATM kinase inhibitor KU-60019radiosensitizes glioma cells,compromises insulin, AKT and ERK prosurvival signaling, and inhibitsmigration and invasion [J]. Molecular cancer therapeutics,2009,8(10):2894-902.
[251] RAINEY M D, CHARLTON M E, STANTON R V, et al.Transient inhibition of ATM kinase is sufficient to enhance cellularsensitivity to ionizing radiation [J]. Cancer research,2008,68(18):7466-74.
[252] RIPOLLES L, ORTEGA M, ORTUNO F, et al. Geneticabnormalities and clinical outcome in chronic lymphocytic leukemia [J].Cancer genetics and cytogenetics,2006,171(1):57-64.
[253] AUSTEN B, SKOWRONSKA A, BAKER C, et al. Mutation statusof the residual ATM allele is an important determinant of the cellularresponse to chemotherapy and survival in patients with chroniclymphocytic leukemia containing an11q deletion [J]. Journal of clinicaloncology: official journal of the American Society of Clinical Oncology,2007,25(34):5448-57.
[254] KHALIL H, TUMMALA H, CHAKAROV S, et al. TargetingATM pathway for therapeutic intervention in cancer [J]. Biodiscovery,2012,1(3.
[255] ROGOFF H A, PICKERING M T, FRAME F M, et al. Apoptosisassociated with deregulated E2F activity is dependent on E2F1andAtm/Nbs1/Chk2[J]. Molecular and cellular biology,2004,24(7):2968-77.
[256] WESTPHAL C H, ROWAN S, SCHMALTZ C, et al. atm and p53cooperate in apoptosis and suppression of tumorigenesis, but not inresistance to acute radiation toxicity [J]. Nature genetics,1997,16(4):397-401.
[257] MAYA R, BALASS M, KIM S T, et al. ATM-dependentphosphorylation of Mdm2on serine395: role in p53activation by DNAdamage [J]. Genes&development,2001,15(9):1067-77.
[258] BASKARAN R, WOOD L D, WHITAKER L L, et al. Ataxiatelangiectasia mutant protein activates c-Abl tyrosine kinase in responseto ionizing radiation [J]. Nature,1997,387(6632):516-9.
[259] WANG J Y. Regulation of cell death by the Abl tyrosine kinase [J].Oncogene,2000,19(49):5643-50.
[260] TRUONG T, SUN G, DOORLY M, et al. Modulation of DNAdamage-induced apoptosis by cell adhesion is independently mediated byp53and c-Abl [J]. Proceedings of the National Academy of Sciences ofthe United States of America,2003,100(18):10281-6.
[261] LOWE S W, SCHMITT E M, SMITH S W, et al. p53is requiredfor radiation-induced apoptosis in mouse thymocytes [J]. Nature,1993,362(6423):847-9.
[262] SAITO S, GOODARZI A A, HIGASHIMOTO Y, et al. ATMmediates phosphorylation at multiple p53sites, including Ser(46), inresponse to ionizing radiation [J]. The Journal of biological chemistry,2002,277(15):12491-4.
[263] HIRAO A, KONG Y Y, MATSUOKA S, et al. DNA damage-induced activation of p53by the checkpoint kinase Chk2[J]. Science,2000,287(5459):1824-7.
[264] BORGES H L, CHAO C, XU Y, et al. Radiation-induced apoptosisin developing mouse retina exhibits dose-dependent requirement forATM phosphorylation of p53[J]. Cell death and differentiation,2004,11(5):494-502.
[265] KARLSEDER J, BROCCOLI D, DAI Y, et al. p53-and ATM-dependent apoptosis induced by telomeres lacking TRF2[J]. Science,1999,283(5406):1321-5.
[266] HERZOG K H, CHONG M J, KAPSETAKI M, et al. Requirementfor Atm in ionizing radiation-induced cell death in the developing centralnervous system [J]. Science,1998,280(5366):1089-91.
[267] CHUNG Y M, PARK S H, TSAI W B, et al. FOXO3signallinglinks ATM to the p53apoptotic pathway following DNA damage [J].Nature communications,2012,3(1000.
[268] POWERS J T, HONG S, MAYHEW C N, et al. E2F1uses theATM signaling pathway to induce p53and Chk2phosphorylation andapoptosis [J]. Molecular cancer research: MCR,2004,2(4):203-14.
[269] LUO L, HUANG W, TAO R, et al. ATM and LKB1dependentactivation of AMPK sensitizes cancer cells to etoposide-inducedapoptosis [J]. Cancer letters,2012,
[270] JIANG H, REINHARDT H C, BARTKOVA J, et al. Thecombined status of ATM and p53link tumor development withtherapeutic response [J]. Genes&development,2009,23(16):1895-909.
[271] LI W, DU B, WANG T, et al. Kaempferol induces apoptosis inhuman HCT116colon cancer cells via the Ataxia-TelangiectasiaMutated-p53pathway with the involvement of p53UpregulatedModulator of Apoptosis [J]. Chemico-biological interactions,2009,177(2):121-7.
[272] LAN Y H, CHIANG J H, HUANG W W, et al. Activations of BothExtrinsic and Intrinsic Pathways in HCT116Human Colorectal CancerCells Contribute to Apoptosis through p53-Mediated ATM/Fas Signalingby Emilia sonchifolia Extract, a Folklore Medicinal Plant [J]. Evidence-based complementary and alternative medicine: eCAM,2012,2012(178178.
[273] GUERRA L, ALBIHN A, TRONNERSJO S, et al. Myc is requiredfor activation of the ATM-dependent checkpoints in response to DNAdamage [J]. PloS one,2010,5(1): e8924.
[274] MERTENS F, JOHANSSON B, MITELMAN F. Isochromosomesin neoplasia [J]. Genes, chromosomes&cancer,1994,10(4):221-30.
[275] WANG J, SU F, SMILENOV L B, et al. Mechanisms of increasedrisk of tumorigenesis in Atm and Brca1double heterozygosity [J]. RadiatOncol,2011,6(96.
[276] SHILOH Y. ATM and ATR: networking cellular responses toDNA damage [J]. Current opinion in genetics&development,2001,11(1):71-7.
[277] PROKOPCOVA J, KLEIBL Z, BANWELL C M, et al. The role ofATM in breast cancer development [J]. Breast cancer research andtreatment,2007,104(2):121-8.
[278] GAO Y, HAYES R B, HUANG W Y, et al. DNA repair genepolymorphisms and tobacco smoking in the risk for colorectal adenomas[J]. Carcinogenesis,2011,32(6):882-7.
[279] ROBERTS N J, JIAO Y, YU J, et al. ATM mutations in patientswith hereditary pancreatic cancer [J]. Cancer discovery,2012,2(1):41-6.
[280] THORSTENSON Y R, ROXAS A, KROISS R, et al.Contributions of ATM mutations to familial breast and ovarian cancer [J].Cancer research,2003,63(12):3325-33.
[281] BRENNAN K, GARCIA-CLOSAS M, ORR N, et al. IntragenicATM methylation in peripheral blood DNA as a biomarker of breastcancer risk [J]. Cancer research,2012,72(9):2304-13.
[282] LI M, FANG X, BAKER D J, et al. The ATM-p53pathwaysuppresses aneuploidy-induced tumorigenesis [J]. Proceedings of theNational Academy of Sciences of the United States of America,2010,107(32):14188-93.
[283] BARTKOVA J, HOREJSI Z, KOED K, et al. DNA damageresponse as a candidate anti-cancer barrier in early human tumorigenesis[J]. Nature,2005,434(7035):864-70.
[284] GORGOULIS V G, VASSILIOU L V, KARAKAIDOS P, et al.Activation of the DNA damage checkpoint and genomic instability inhuman precancerous lesions [J]. Nature,2005,434(7035):907-13.
[285] YAMAMOTO K, WANG Y, JIANG W, et al. Kinase-dead ATMprotein causes genomic instability and early embryonic lethality in mice[J]. The Journal of cell biology,2012,198(3):305-13.
[286] DANIEL J A, PELLEGRINI M, LEE B S, et al. Loss of ATMkinase activity leads to embryonic lethality in mice [J]. The Journal ofcell biology,2012,198(3):295-304.
[287] SHILOH Y, ZIV Y. The ATM protein: The importance of beingactive [J]. The Journal of cell biology,2012,198(3):273-5.
[288] HU H, DU L, NAGABAYASHI G, et al. ATM is down-regulatedby N-Myc-regulated microRNA-421[J]. Proceedings of the NationalAcademy of Sciences of the United States of America,2010,107(4):1506-11.
[289] YAN D, NG W L, ZHANG X, et al. Targeting DNA-PKcs andATM with miR-101sensitizes tumors to radiation [J]. PloS one,2010,5(7): e11397.
[290] NG W L, YAN D, ZHANG X, et al. Over-expression of miR-100is responsible for the low-expression of ATM in the human glioma cellline: M059J [J]. DNA repair,2010,9(11):1170-5.
[291] MORIN R D, O'CONNOR M D, GRIFFITH M, et al. Applicationof massively parallel sequencing to microRNA profiling and discovery inhuman embryonic stem cells [J]. Genome research,2008,18(4):610-21.
[292] MA F, LIU X, LI D, et al. MicroRNA-466l upregulates IL-10expression in TLR-triggered macrophages by antagonizing RNA-bindingprotein tristetraprolin-mediated IL-10mRNA degradation [J]. J Immunol,2010,184(11):6053-9.
[293] LI L C, OKINO S T, ZHAO H, et al. Small dsRNAs inducetranscriptional activation in human cells [J]. Proceedings of the NationalAcademy of Sciences of the United States of America,2006,103(46):17337-42.
[294] JANOWSKI B A, YOUNGER S T, HARDY D B, et al. Activatinggene expression in mammalian cells with promoter-targeted duplexRNAs [J]. Nature chemical biology,2007,3(3):166-73.
[295] PLACE R F, LI L C, POOKOT D, et al. MicroRNA-373inducesexpression of genes with complementary promoter sequences [J].Proceedings of the National Academy of Sciences of the United States ofAmerica,2008,105(5):1608-13.
[296] HUANG V, PLACE R F, PORTNOY V, et al. Upregulation ofCyclin B1by miRNA and its implications in cancer [J]. Nucleic acidsresearch,2012,40(4):1695-707.
[297] OROM U A, NIELSEN F C, LUND A H. MicroRNA-10a bindsthe5'UTR of ribosomal protein mRNAs and enhances their translation [J].Molecular cell,2008,30(4):460-71.
[298] JOPLING C L, YI M, LANCASTER A M, et al. Modulation ofhepatitis C virus RNA abundance by a liver-specific MicroRNA [J].Science,2005,309(5740):1577-81.
[299] ROBERTS A P, LEWIS A P, JOPLING C L. miR-122activateshepatitis C virus translation by a specialized mechanism requiringparticular RNA components [J]. Nucleic acids research,2011,39(17):7716-29.
[300] COLLER H A, SANG L, ROBERTS J M. A new description ofcellular quiescence [J]. PLoS biology,2006,4(3): e83.
[301] VASUDEVAN S. Posttranscriptional upregulation by microRNAs[J]. Wiley interdisciplinary reviews RNA,2012,3(3):311-30.
[302] VASUDEVAN S, STEITZ J A. AU-rich-element-mediatedupregulation of translation by FXR1and Argonaute2[J]. Cell,2007,128(6):1105-18.
[303] VASUDEVAN S, TONG Y, STEITZ J A. Switching fromrepression to activation: microRNAs can up-regulate translation [J].Science,2007,318(5858):1931-4.
[304] VASUDEVAN S, TONG Y, STEITZ J A. Cell-cycle control ofmicroRNA-mediated translation regulation [J]. Cell Cycle,2008,7(11):1545-9.
[305] MORTENSEN R D, SERRA M, STEITZ J A, et al.Posttranscriptional activation of gene expression in Xenopus laevisoocytes by microRNA-protein complexes (microRNPs)[J]. Proceedingsof the National Academy of Sciences of the United States of America,2011,108(20):8281-6.
[306] LEIVONEN S K, MAKELA R, OSTLING P, et al. Protein lysatemicroarray analysis to identify microRNAs regulating estrogen receptorsignaling in breast cancer cell lines [J]. Oncogene,2009,28(44):3926-36.
[307] SONG L, LIN C, WU Z, et al. miR-18a impairs DNA damageresponse through downregulation of ataxia telangiectasia mutated (ATM)kinase [J]. PloS one,2011,6(9): e25454.
[308] WICKRAMASINGHE N S, MANAVALAN T T, DOUGHERTYS M, et al. Estradiol downregulates miR-21expression and increasesmiR-21target gene expression in MCF-7breast cancer cells [J]. Nucleicacids research,2009,37(8):2584-95.
[309] DONG J, ZHAO Y P, ZHOU L, et al. Bcl-2upregulation inducedby miR-21via a direct interaction is associated with apoptosis andchemoresistance in MIA PaCa-2pancreatic cancer cells [J]. Archives ofmedical research,2011,42(1):8-14.
[310] LIN C C, LIU L Z, ADDISON J B, et al. A KLF4-miRNA-206autoregulatory feedback loop can promote or inhibit protein translationdepending upon cell context [J]. Molecular and cellular biology,2011,31(12):2513-27.
[311] NIEMOELLER O M, NIYAZI M, CORRADINI S, et al.MicroRNA expression profiles in human cancer cells after ionizingradiation [J]. Radiat Oncol,2011,6(29.
[312] GIRARDI C, DE PITTA C, CASARA S, et al. Analysis of miRNAand mRNA expression profiles highlights alterations in ionizing radiationresponse of human lymphocytes under modeled microgravity [J]. PloSone,2012,7(2): e31293.
[313] CHA H J, SHIN S, YOO H, et al. Identification of ionizingradiation-responsive microRNAs in the IM9human B lymphoblastic cellline [J]. International journal of oncology,2009,34(6):1661-8.
[314] SHIN S, CHA H J, LEE E M, et al. Alteration of miRNA profilesby ionizing radiation in A549human non-small cell lung cancer cells [J].International journal of oncology,2009,35(1):81-6.
[315] NIKIFOROVA M N, GANDHI M, KELLY L, et al. MicroRNAdysregulation in human thyroid cells following exposure to ionizingradiation [J]. Thyroid: official journal of the American ThyroidAssociation,2011,21(3):261-6.
[316] CHAUDHRY M A. Real-time PCR analysis of micro-RNAexpression in ionizing radiation-treated cells [J]. Cancer biotherapy&radiopharmaceuticals,2009,24(1):49-56.
[317] ZHU Y, YU X, FU H, et al. MicroRNA-21is involved in ionizingradiation-promoted liver carcinogenesis [J]. International journal ofclinical and experimental medicine,2010,3(3):211-22.
[318] LIANG Z, AHN J, GUO D, et al. MicroRNA-302ReplacementTherapy Sensitizes Breast Cancer Cells to Ionizing Radiation [J].Pharmaceutical research,2012,
[319] SIMONE N L, SOULE B P, LY D, et al. Ionizing radiation-induced oxidative stress alters miRNA expression [J]. PloS one,2009,4(7): e6377.
[320] CHAUDHRY M A, OMARUDDIN R A. Differential regulation ofmicroRNA expression in irradiated and bystander cells [J].Molekuliarnaia biologiia,2012,46(4):634-43.
[321] KULSHRESHTHA R, FERRACIN M, WOJCIK S E, et al. AmicroRNA signature of hypoxia [J]. Molecular and cellular biology,2007,27(5):1859-67.
[322] O'CONNELL R M, TAGANOV K D, BOLDIN M P, et al.MicroRNA-155is induced during the macrophage inflammatory response[J]. Proceedings of the National Academy of Sciences of the UnitedStates of America,2007,104(5):1604-9.
[323] LEE H J, PALKOVITS M, YOUNG W S,3RD. miR-7b, amicroRNA up-regulated in the hypothalamus after chronic hyperosmolarstimulation, inhibits Fos translation [J]. Proceedings of the NationalAcademy of Sciences of the United States of America,2006,103(42):15669-74.
[324] SALEH A D, SAVAGE J E, CAO L, et al. Cellular stress inducedalterations in microRNA let-7a and let-7b expression are dependent onp53[J]. PloS one,2011,6(10): e24429.
[325] TRABUCCHI M, BRIATA P, GARCIA-MAYORAL M, et al. TheRNA-binding protein KSRP promotes the biogenesis of a subset ofmicroRNAs [J]. Nature,2009,459(7249):1010-4.
[326] TRABUCCHI M, BRIATA P, FILIPOWICZ W, et al. KSRPpromotes the maturation of a group of miRNA precursors [J]. Advancesin experimental medicine and biology,2010,700(36-42.
[327] ZHANG X, WAN G, BERGER F G, et al. The ATM kinaseinduces microRNA biogenesis in the DNA damage response [J].Molecular cell,2011,41(4):371-83.
[328] LEUNG A K, SHARP P A. MicroRNA functions in stressresponses [J]. Molecular cell,2010,40(2):205-15.
[329] MARSIT C J, EDDY K, KELSEY K T. MicroRNA responses tocellular stress [J]. Cancer research,2006,66(22):10843-8.
[330] HUO J, QIN F, CAI X, et al. Chinese medicine formula "WeikangKeli" induces autophagic cell death on human gastric cancer cell lineSGC-7901[J]. Phytomedicine: international journal of phytotherapy andphytopharmacology,2012,
[331] SHIMIZU S, KANASEKI T, MIZUSHIMA N, et al. Role of Bcl-2family proteins in a non-apoptotic programmed cell death dependent onautophagy genes [J]. Nature cell biology,2004,6(12):1221-8.
[332] ESPERT L, DENIZOT M, GRIMALDI M, et al. Autophagy isinvolved in T cell death after binding of HIV-1envelope proteins toCXCR4[J]. The Journal of clinical investigation,2006,116(8):2161-72.
[333] SALAZAR M, CARRACEDO A, SALANUEVA I J, et al.Cannabinoid action induces autophagy-mediated cell death throughstimulation of ER stress in human glioma cells [J]. The Journal of clinicalinvestigation,2009,119(5):1359-72.
[334] QU X, ZOU Z, SUN Q, et al. Autophagy gene-dependent clearanceof apoptotic cells during embryonic development [J]. Cell,2007,128(5):931-46.
[335] LEMASTERS J J. Selective mitochondrial autophagy, ormitophagy, as a targeted defense against oxidative stress, mitochondrialdysfunction, and aging [J]. Rejuvenation research,2005,8(1):3-5.
[336] DING W X, NI H M, GAO W, et al. Linking of autophagy toubiquitin-proteasome system is important for the regulation ofendoplasmic reticulum stress and cell viability [J]. The American journalof pathology,2007,171(2):513-24.
[337] OGATA M, HINO S, SAITO A, et al. Autophagy is activated forcell survival after endoplasmic reticulum stress [J]. Molecular andcellular biology,2006,26(24):9220-31.
[338] BERNALES S, MCDONALD K L, WALTER P. Autophagycounterbalances endoplasmic reticulum expansion during the unfoldedprotein response [J]. PLoS biology,2006,4(12): e423.
[339] KOMATSU M, WAGURI S, UENO T, et al. Impairment ofstarvation-induced and constitutive autophagy in Atg7-deficient mice [J].The Journal of cell biology,2005,169(3):425-34.
[340] KUMA A, HATANO M, MATSUI M, et al. The role of autophagyduring the early neonatal starvation period [J]. Nature,2004,432(7020):1032-6.
[341] BOYA P, GONZALEZ-POLO R A, CASARES N, et al. Inhibitionof macroautophagy triggers apoptosis [J]. Molecular and cellular biology,2005,25(3):1025-40.
[342] GONZALEZ-POLO R A, BOYA P, PAULEAU A L, et al. Theapoptosis/autophagy paradox: autophagic vacuolization before apoptoticdeath [J]. Journal of cell science,2005,118(Pt14):3091-102.
[343] GUMP J M, THORBURN A. Autophagy and apoptosis: what isthe connection?[J]. Trends in cell biology,2011,21(7):387-92.
[344] DEGENHARDT K, MATHEW R, BEAUDOIN B, et al.Autophagy promotes tumor cell survival and restricts necrosis,inflammation, and tumorigenesis [J]. Cancer cell,2006,10(1):51-64.
[345] SAMARA C, SYNTICHAKI P, TAVERNARAKIS N. Autophagyis required for necrotic cell death in Caenorhabditis elegans [J]. Celldeath and differentiation,2008,15(1):105-12.
[346] KROEMER G, MARINO G, LEVINE B. Autophagy and theintegrated stress response [J]. Molecular cell,2010,40(2):280-93.
[347] HIPPERT M M, O'TOOLE P S, THORBURN A. Autophagy incancer: good, bad, or both?[J]. Cancer research,2006,66(19):9349-51.
[348] EISENBERG-LERNER A, KIMCHI A. The paradox of autophagyand its implication in cancer etiology and therapy [J]. Apoptosis: aninternational journal on programmed cell death,2009,14(4):376-91.
[349] GEWIRTZ D A, HILLIKER M L, WILSON E N. Promotion ofautophagy as a mechanism for radiation sensitization of breast tumor cells[J]. Radiotherapy and oncology: journal of the European Society forTherapeutic Radiology and Oncology,2009,92(3):323-8.
[350] ZOIS C E, KOUKOURAKIS M I. Radiation-induced autophagy innormal and cancer cells: towards novel cytoprotection and radio-sensitization policies?[J]. Autophagy,2009,5(4):442-50.
[351] CAO C, SUBHAWONG T, ALBERT J M, et al. Inhibition ofmammalian target of rapamycin or apoptotic pathway induces autophagyand radiosensitizes PTEN null prostate cancer cells [J]. Cancer research,2006,66(20):10040-7.
[352] MORETTI L, ATTIA A, KIM K W, et al. Crosstalk betweenBak/Bax and mTOR signaling regulates radiation-induced autophagy [J].Autophagy,2007,3(2):142-4.
[353] YUK J M, SHIN D M, SONG K S, et al. Bacillus calmette-guerincell wall cytoskeleton enhances colon cancer radiosensitivity throughautophagy [J]. Autophagy,2010,6(1):46-60.
[354] PAN J, CHEN B, SU C H, et al. Autophagy induced byfarnesyltransferase inhibitors in cancer cells [J]. Cancer biology&therapy,2008,7(10):1679-84.
[355] SMITH E L, SCHUCHMAN E H. Acid sphingomyelinaseoverexpression enhances the antineoplastic effects of irradiation in vitroand in vivo [J]. Molecular therapy: the journal of the American Societyof Gene Therapy,2008,16(9):1565-71.
[356] DEMASTERS G, DI X, NEWSHAM I, et al. Potentiation ofradiation sensitivity in breast tumor cells by the vitamin D3analogue, EB1089, through promotion of autophagy and interference with proliferativerecovery [J]. Molecular cancer therapeutics,2006,5(11):2786-97.
[357] TSUBOI Y, KURIMOTO M, NAGAI S, et al. Induction ofautophagic cell death and radiosensitization by the pharmacologicalinhibition of nuclear factor-kappa B activation in human glioma cell lines[J]. Journal of neurosurgery,2009,110(3):594-604.
[358] CHAACHOUAY H, OHNESEIT P, TOULANY M, et al.Autophagy contributes to resistance of tumor cells to ionizing radiation[J]. Radiotherapy and oncology: journal of the European Society forTherapeutic Radiology and Oncology,2011,99(3):287-92.
[359] LOMONACO S L, FINNISS S, XIANG C, et al. The induction ofautophagy by gamma-radiation contributes to the radioresistance ofglioma stem cells [J]. International journal of cancer Journal internationaldu cancer,2009,125(3):717-22.
[360] APEL A, HERR I, SCHWARZ H, et al. Blocked autophagysensitizes resistant carcinoma cells to radiation therapy [J]. Cancerresearch,2008,68(5):1485-94.
[361] NOTTE A, LECLERE L, MICHIELS C. Autophagy as a mediatorof chemotherapy-induced cell death in cancer [J]. Biochemicalpharmacology,2011,82(5):427-34.
[362] XIONG H Y, GUO X L, BU X X, et al. Autophagic cell deathinduced by5-FU in Bax or PUMA deficient human colon cancer cell [J].Cancer letters,2010,288(1):68-74.
[363] LI J, HOU N, FARIED A, et al. Inhibition of autophagy augments5-fluorouracil chemotherapy in human colon cancer in vitro and in vivomodel [J]. Eur J Cancer,2010,46(10):1900-9.
[364] MIKI H, UEHARA N, KIMURA A, et al. Resveratrol inducesapoptosis via ROS-triggered autophagy in human colon cancer cells [J].International journal of oncology,2012,40(4):1020-8.
[365] LEE Y J, KIM N Y, SUH Y A, et al. Involvement of ROS inCurcumin-induced Autophagic Cell Death [J]. The Korean journal ofphysiology&pharmacology: official journal of the Korean PhysiologicalSociety and the Korean Society of Pharmacology,2011,15(1):1-7.
[366] JOHN S, MLS J, CERVINKA M, et al. The Role of AutophagicCell Death and Apoptosis in Irinotecan-Treated P53Null Colon CancerCells [J]. Anti-cancer agents in medicinal chemistry,2012,
[367] MARTIN A P, MITCHELL C, RAHMANI M, et al. Inhibition ofMCL-1enhances lapatinib toxicity and overcomes lapatinib resistance viaBAK-dependent autophagy [J]. Cancer biology&therapy,2009,8(21):2084-96.
[368] VERDOODT B, VOGT M, SCHMITZ I, et al. Salinomycininduces autophagy in colon and breast cancer cells with concomitantgeneration of reactive oxygen species [J]. PloS one,2012,7(9): e44132.
[369] XIE C M, CHAN W Y, YU S, et al. Bufalin induces autophagy-mediated cell death in human colon cancer cells through reactive oxygenspecies generation and JNK activation [J]. Free radical biology&medicine,2011,51(7):1365-75.
[370] SHINGU T, FUJIWARA K, BOGLER O, et al. Stage-specificeffect of inhibition of autophagy on chemotherapy-induced cytotoxicity[J]. Autophagy,2009,5(4):537-9.
[371] ZHOU S, ZHAO L, KUANG M, et al. Autophagy in tumorigenesisand cancer therapy: Dr. Jekyll or Mr. Hyde?[J]. Cancer letters,2012,323(2):115-27.
[372] HOYER-HANSEN M, JAATTELA M. Autophagy: an emergingtarget for cancer therapy [J]. Autophagy,2008,4(5):574-80.
[373] ZHU H, WU H, LIU X, et al. Regulation of autophagy by a beclin1-targeted microRNA, miR-30a, in cancer cells [J]. Autophagy,2009,5(6):816-23.
[374] ZOU Z, WU L, DING H, et al. MicroRNA-30a sensitizes tumorcells to cis-platinum via suppressing beclin1-mediated autophagy [J].The Journal of biological chemistry,2012,287(6):4148-56.
[375] KORKMAZ G, LE SAGE C, TEKIRDAG K A, et al. miR-376bcontrols starvation and mTOR inhibition-related autophagy by targetingATG4C and BECN1[J]. Autophagy,2012,8(2):165-76.
[376] YU Y, CAO L, YANG L, et al. microRNA30A promotesautophagy in response to cancer therapy [J]. Autophagy,2012,8(5):853-5.
[377] KOVALEVA V, MORA R, PARK Y J, et al. miRNA-130a targetsATG2B and DICER1to inhibit autophagy and trigger killing of chroniclymphocytic leukemia cells [J]. Cancer research,2012,72(7):1763-72.
[378] XIAO J, ZHU X, HE B, et al. MiR-204regulates cardiomyocyteautophagy induced by ischemia-reperfusion through LC3-II [J]. Journalof biomedical science,2011,18(35.
[379] UCAR A, GUPTA S K, FIEDLER J, et al. The miRNA-212/132family regulates both cardiac hypertrophy and cardiomyocyte autophagy[J]. Nature communications,2012,3(1078.
[380] FRANKEL L B, WEN J, LEES M, et al. microRNA-101is apotent inhibitor of autophagy [J]. The EMBO journal,2011,30(22):4628-41.
[381] CHANG Y, YAN W, HE X, et al. miR-375inhibits autophagy andreduces viability of hepatocellular carcinoma cells under hypoxicconditions [J]. Gastroenterology,2012,143(1):177-87e8.
[382] CHEN Y, LIERSCH R, DETMAR M. The miR-290-295clustersuppresses autophagic cell death of melanoma cells [J]. Scientific reports,2012,2(808.
[383] TSUCHIDA A, OHNO S, WU W, et al. miR-92is a key oncogeniccomponent of the miR-17-92cluster in colon cancer [J]. Cancer science,2011,102(12):2264-71.
[384] CORRADETTI M N, GUAN K L. Upstream of the mammaliantarget of rapamycin: do all roads pass through mTOR?[J]. Oncogene,2006,25(48):6347-60.
[385] MATHEW R, KARP C M, BEAUDOIN B, et al. Autophagysuppresses tumorigenesis through elimination of p62[J]. Cell,2009,137(6):1062-75.
[386] MOSCAT J, DIAZ-MECO M T. p62at the crossroads ofautophagy, apoptosis, and cancer [J]. Cell,2009,137(6):1001-4.
[387] PUISSANT A, FENOUILLE N, AUBERGER P. When autophagymeets cancer through p62/SQSTM1[J]. American journal of cancerresearch,2012,2(4):397-413.
[388] WANG Z, CAO L, KANG R, et al. Autophagy regulates myeloidcell differentiation by p62/SQSTM1-mediated degradation of PML-RARalpha oncoprotein [J]. Autophagy,2011,7(4):401-11.
[389] YANG Z J, CHEE C E, HUANG S, et al. Autophagy modulationfor cancer therapy [J]. Cancer biology&therapy,2011,11(2):169-76.
[390] BOHENSKY J, SHAPIRO I M, LESHINSKY S, et al. HIF-1regulation of chondrocyte apoptosis: induction of the autophagic pathway[J]. Autophagy,2007,3(3):207-14.
[391] ZHANG H, BOSCH-MARCE M, SHIMODA L A, et al.Mitochondrial autophagy is an HIF-1-dependent adaptive metabolicresponse to hypoxia [J]. The Journal of biological chemistry,2008,283(16):10892-903.
[392] BELIBI F, ZAFAR I, RAVICHANDRAN K, et al. Hypoxia-inducible factor-1alpha (HIF-1alpha) and autophagy in polycystic kidneydisease (PKD)[J]. American journal of physiology Renal physiology,2011,300(5): F1235-43.
[393] ZHAO Y, CHEN G, ZHANG W, et al. Autophagy regulateshypoxia-induced osteoclastogenesis through the HIF-1alpha/BNIP3signaling pathway [J]. Journal of cellular physiology,2012,227(2):639-48.
[394] BOSSEL BEN-MOSHE N, AVRAHAM R, KEDMI M, et al.Context-specific microRNA analysis: identification of functionalmicroRNAs and their mRNA targets [J]. Nucleic acids research,2012,40(21):10614-27.
[395] WEIDHAAS J B, BABAR I, NALLUR S M, et al. MicroRNAs aspotential agents to alter resistance to cytotoxic anticancer therapy [J].Cancer research,2007,67(23):11111-6.
[396] JOSSON S, SUNG S Y, LAO K, et al. Radiation modulation ofmicroRNA in prostate cancer cell lines [J]. The Prostate,2008,68(15):1599-606.
[397] GLIMELIUS B. Radiotherapy in rectal cancer [J]. British medicalbulletin,2002,64(141-57.
[398] GRABSCH H, DATTANI M, BARKER L, et al. Expression ofDNA double-strand break repair proteins ATM and BRCA1predictssurvival in colorectal cancer [J]. Clinical cancer research: an officialjournal of the American Association for Cancer Research,2006,12(5):1494-500.
[399] BEGGS A D, DOMINGO E, MCGREGOR M, et al. Loss ofexpression of the double strand break repair protein ATM is associatedwith worse prognosis in colorectal cancer and loss of Ku70expression isassociated with CIN [J]. Oncotarget,2012,3(11):1348-55.
[400] WU Y, LIU G L, LIU S H, et al. MicroRNA-148b enhances theradiosensitivity of non-Hodgkin's Lymphoma cells by promotingradiation-induced apoptosis [J]. Journal of radiation research,2012,53(4):516-25.
[401] HUANG S, LI X Q, CHEN X, et al. Inhibition of microRNA-21increases radiosensitivity of esophageal cancer cells through phosphataseand tensin homolog deleted on chromosome10activation [J]. Diseases ofthe esophagus: official journal of the International Society for Diseasesof the Esophagus/ISDE,2012,
[402] ZHANG S, WAN Y, PAN T, et al. MicroRNA-21inhibitorsensitizes human glioblastoma U251stem cells to chemotherapeutic drugtemozolomide [J]. Journal of molecular neuroscience: MN,2012,47(2):346-56.
[403] LEE K M, CHOI E J, KIM I A. microRNA-7increasesradiosensitivity of human cancer cells with activated EGFR-associatedsignaling [J]. Radiotherapy and oncology: journal of the EuropeanSociety for Therapeutic Radiology and Oncology,2011,101(1):171-6.
[404] NASSER M W, DATTA J, NUOVO G, et al. Down-regulation ofmicro-RNA-1(miR-1) in lung cancer. Suppression of tumorigenicproperty of lung cancer cells and their sensitization to doxorubicin-induced apoptosis by miR-1[J]. The Journal of biological chemistry,2008,283(48):33394-405.
[405] XIA L, ZHANG D, DU R, et al. miR-15b and miR-16modulatemultidrug resistance by targeting BCL2in human gastric cancer cells [J].International journal of cancer Journal international du cancer,2008,123(2):372-9.
[406] HUMMEL R, HUSSEY D J, HAIER J. MicroRNAs: predictorsand modifiers of chemo-and radiotherapy in different tumour types [J].Eur J Cancer,2010,46(2):298-311.
[407] HAYASHITA Y, OSADA H, TATEMATSU Y, et al. Apolycistronic microRNA cluster, miR-17-92, is overexpressed in humanlung cancers and enhances cell proliferation [J]. Cancer research,2005,65(21):9628-32.
[408] OTA A, TAGAWA H, KARNAN S, et al. Identification andcharacterization of a novel gene, C13orf25, as a target for13q31-q32amplification in malignant lymphoma [J]. Cancer research,2004,64(9):3087-95.
[409] HERMSEN M, POSTMA C, BAAK J, et al. Colorectal adenoma tocarcinoma progression follows multiple pathways of chromosomalinstability [J]. Gastroenterology,2002,123(4):1109-19.
[410] TANZER A, STADLER P F. Molecular evolution of a microRNAcluster [J]. Journal of molecular biology,2004,339(2):327-35.
[411] HE L, THOMSON J M, HEMANN M T, et al. A microRNApolycistron as a potential human oncogene [J]. Nature,2005,435(7043):828-33.
[412] XIANG J, WU J. Feud or Friend? The Role of the miR-17-92Cluster in Tumorigenesis [J]. Current genomics,2010,11(2):129-35.
[413] YU G, TANG J Q, TIAN M L, et al. Prognostic values of the miR-17-92cluster and its paralogs in colon cancer [J]. Journal of surgicaloncology,2012,106(3):232-7.
[414] STEMBALSKA A, BLIN N, RAMSEY D, et al. Three distinctregions of deletion on13q in squamous cell carcinoma of the larynx [J].Oncology reports,2006,16(2):417-21.
[415] ZHANG X L, FU W L, ZHAO H X, et al. Molecular studies of lossof heterozygosity in Chinese sporadic retinoblastoma patients [J]. Clinicachimica acta; international journal of clinical chemistry,2005,358(1-2):75-80.
[416] LIN Y W, SHEU J C, LIU L Y, et al. Loss of heterozygosity atchromosome13q in hepatocellular carcinoma: identification of threeindependent regions [J]. Eur J Cancer,1999,35(12):1730-4.
[417] EIRIKSDOTTIR G, JOHANNESDOTTIR G, INGVARSSON S,et al. Mapping loss of heterozygosity at chromosome13q: loss at13q12-q13is associated with breast tumour progression and poor prognosis [J].Eur J Cancer,1998,34(13):2076-81.
[418] LO K W, TEO P M, HUI A B, et al. High resolution allelotype ofmicrodissected primary nasopharyngeal carcinoma [J]. Cancer research,2000,60(13):3348-53.
[419] ZHANG L, HUANG J, YANG N, et al. microRNAs exhibit highfrequency genomic alterations in human cancer [J]. Proceedings of theNational Academy of Sciences of the United States of America,2006,103(24):9136-41.
[420] OLIVE V, JIANG I, HE L. mir-17-92, a cluster of miRNAs in themidst of the cancer network [J]. The international journal of biochemistry&cell biology,2010,42(8):1348-54.
[421] LI T, CHEN J X, FU X P, et al. microRNA expression profiling ofnasopharyngeal carcinoma [J]. Oncology reports,2011,25(5):1353-63.
[422] YAO Y, SUO A L, LI Z F, et al. MicroRNA profiling of humangastric cancer [J]. Molecular medicine reports,2009,2(6):963-70.
[423] ALENCAR A J, MALUMBRES R, KOZLOSKI G A, et al.MicroRNAs are independent predictors of outcome in diffuse large B-celllymphoma patients treated with R-CHOP [J]. Clinical cancer research: anofficial journal of the American Association for Cancer Research,2011,17(12):4125-35.
[424] AYALA DE LA PENA F, KANASAKI K, KANASAKI M, et al.Loss of p53and acquisition of angiogenic microRNA profile areinsufficient to facilitate progression of bladder urothelial carcinoma insitu to invasive carcinoma [J]. The Journal of biological chemistry,2011,286(23):20778-87.
[425] MOTOYAMA K, INOUE H, TAKATSUNO Y, et al. Over-andunder-expressed microRNAs in human colorectal cancer [J]. Internationaljournal of oncology,2009,34(4):1069-75.
[426] MORIMURA R, KOMATSU S, ICHIKAWA D, et al. Noveldiagnostic value of circulating miR-18a in plasma of patients withpancreatic cancer [J]. British journal of cancer,2011,105(11):1733-40.
[427] LOVEN J, ZININ N, WAHLSTROM T, et al. MYCN-regulatedmicroRNAs repress estrogen receptor-alpha (ESR1) expression andneuronal differentiation in human neuroblastoma [J]. Proceedings of theNational Academy of Sciences of the United States of America,2010,107(4):1553-8.
[428] LIU W H, YEH S H, LU C C, et al. MicroRNA-18a preventsestrogen receptor-alpha expression, promoting proliferation ofhepatocellular carcinoma cells [J]. Gastroenterology,2009,136(2):683-93.
[429] TAO J, WU D, LI P, et al. microRNA-18a, a member of theoncogenic miR-17-92cluster, targets Dicer and suppresses cellproliferation in bladder cancer T24cells [J]. Molecular medicine reports,2012,5(1):167-72.
[430] LUO Z, DAI Y, ZHANG L, et al. miR-18a promotes malignantprogression by impairing microRNA biogenesis in nasopharyngealcarcinoma [J]. Carcinogenesis,2012,
[431] FOX J L, DEWS M, MINN A J, et al. Targeting of TGFbetasignature and its essential component CTGF by miR-18correlates withimproved survival in glioblastoma [J]. RNA,2012,
[432] YAMADA N A, CASTRO A, FARBER R A. Variation in theextent of microsatellite instability in human cell lines with defects indifferent mismatch repair genes [J]. Mutagenesis,2003,18(3):277-82.
[433] YEUNG T M, GANDHI S C, WILDING J L, et al. Cancer stemcells from colorectal cancer-derived cell lines [J]. Proceedings of theNational Academy of Sciences of the United States of America,2010,107(8):3722-7.
[434] HUMPHREYS K J, COBIAC L, LE LEU R K, et al. Histonedeacetylase inhibition in colorectal cancer cells reveals competing rolesfor members of the oncogenic miR-17-92cluster [J]. Molecularcarcinogenesis,2012,
[435] LI Y, BAVARVA J H, WANG Z, et al. HEF1, a novel target ofWnt signaling, promotes colonic cell migration and cancer progression [J].Oncogene,2011,30(23):2633-43.
[436] XIA D, HOLLA V R, WANG D, et al. HEF1is a crucial mediatorof the proliferative effects of prostaglandin E(2) on colon cancer cells [J].Cancer research,2010,70(2):824-31.
[437] MALUMBRES M, HARLOW E, HUNT T, et al. Cyclin-dependent kinases: a family portrait [J]. Nature cell biology,2009,11(11):1275-6.
[438] FIRESTEIN R, BASS A J, KIM S Y, et al. CDK8is a colorectalcancer oncogene that regulates beta-catenin activity [J]. Nature,2008,455(7212):547-51.
[439] SHEN K C, HENG H, WANG Y, et al. ATM and p21cooperate tosuppress aneuploidy and subsequent tumor development [J]. Cancerresearch,2005,65(19):8747-53.
[440]JIEMJIT A, FANDY T E, CARRAWAY H, et al. p21(WAF1/CIP1)induction by5-azacytosine nucleosides requires DNA damage [J].Oncogene,2008,27(25):3615-23.
[441] TSANG W P, KWOK T T. The miR-18a*microRNA functions asa potential tumor suppressor by targeting on K-Ras [J]. Carcinogenesis,2009,30(6):953-9.
[442] ZHANG J, XIAO Z, LAI D, et al. miR-21, miR-17and miR-19ainduced by phosphatase of regenerating liver-3promote the proliferationand metastasis of colon cancer [J]. British journal of cancer,2012,107(2):352-9.
[443] OLIVE V, BENNETT M J, WALKER J C, et al. miR-19is a keyoncogenic component of mir-17-92[J]. Genes&development,2009,23(24):2839-49.
[444] CASTELLANO L, GIAMAS G, JACOB J, et al. The estrogenreceptor-alpha-induced microRNA signature regulates itself and itstranscriptional response [J]. Proceedings of the National Academy ofSciences of the United States of America,2009,106(37):15732-7.
[445] HAGGAR F A, BOUSHEY R P. Colorectal cancer epidemiology:incidence, mortality, survival, and risk factors [J]. Clinics in colon andrectal surgery,2009,22(4):191-7.
[446] RAJAGOPALAN H, NOWAK M A, VOGELSTEIN B, et al. Thesignificance of unstable chromosomes in colorectal cancer [J]. Naturereviews Cancer,2003,3(9):695-701.
[447] BARTKOVA J, REZAEI N, LIONTOS M, et al. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNAdamage checkpoints [J]. Nature,2006,444(7119):633-7.
[448] GORGOULIS V G, HALAZONETIS T D. Oncogene-inducedsenescence: the bright and dark side of the response [J]. Current opinionin cell biology,2010,22(6):816-27.
[449] KWONG L N, WEISS K R, HAIGIS K M, et al. Atm is a negativeregulator of intestinal neoplasia [J]. Oncogene,2008,27(7):1013-8.
[450] GAO C, CAO W, BAO L, et al. Autophagy negatively regulatesWnt signalling by promoting Dishevelled degradation [J]. Nature cellbiology,2010,12(8):781-90.
[451] POLAKIS P. Wnt signaling in cancer [J]. Cold Spring Harborperspectives in biology,2012,4(5):
[452] BAKIRTZI K, HATZIAPOSTOLOU M, KARAGIANNIDES I, etal. Neurotensin signaling activates microRNAs-21and-155and Akt,promotes tumor growth in mice, and is increased in human colon tumors[J]. Gastroenterology,2011,141(5):1749-61e1.
[453] COTTONHAM C L, KANEKO S, XU L. miR-21and miR-31converge on TIAM1to regulate migration and invasion of coloncarcinoma cells [J]. The Journal of biological chemistry,2010,285(46):35293-302.
[454] FALTEJSKOVA P, BESSE A, SEVCIKOVA S, et al. Clinicalcorrelations of miR-21expression in colorectal cancer patients and effectsof its inhibition on DLD1colon cancer cells [J]. International journal ofcolorectal disease,2012,27(11):1401-8.
[455] WU J, WU G, LV L, et al. MicroRNA-34a inhibits migration andinvasion of colon cancer cells via targeting to Fra-1[J]. Carcinogenesis,2012,33(3):519-28.
[456] CAMPANER S, AMATI B. Two sides of the Myc-induced DNAdamage response: from tumor suppression to tumor maintenance [J]. Celldivision,2012,7(1):6.
[457] PUSAPATI R V, ROUNBEHLER R J, HONG S, et al. ATMpromotes apoptosis and suppresses tumorigenesis in response to Myc [J].Proceedings of the National Academy of Sciences of the United States ofAmerica,2006,103(5):1446-51.
[458] VAN HAAFTEN G, AGAMI R. Tumorigenicity of the miR-17-92cluster distilled [J]. Genes&development,2010,24(1):1-4.
[2] MIZUSHIMA N. Autophagy: process and function [J]. Genes&development,2007,21(22):2861-73.
[3] SAHU R, KAUSHIK S, CLEMENT C C, et al. Microautophagy ofcytosolic proteins by late endosomes [J]. Developmental cell,2011,20(1):131-9.
[4] LI W, YANG Q, MAO Z. Chaperone-mediated autophagy:machinery, regulation and biological consequences [J]. Cellular andmolecular life sciences: CMLS,2011,68(5):749-63.
[5] MIZUSHIMA N, LEVINE B, CUERVO A M, et al. Autophagyfights disease through cellular self-digestion [J]. Nature,2008,451(7182):1069-75.
[6] CHEN Y, KLIONSKY D J. The regulation of autophagy-unanswered questions [J]. Journal of cell science,2011,124(Pt2):161-70.
[7] LEVINE B, KROEMER G. Autophagy in the pathogenesis ofdisease [J]. Cell,2008,132(1):27-42.
[8] SHINTANI T, KLIONSKY D J. Autophagy in health and disease:a double-edged sword [J]. Science,2004,306(5698):990-5.
[9] GONZALEZ C D, LEE M S, MARCHETTI P, et al. The emergingrole of autophagy in the pathophysiology of diabetes mellitus [J].Autophagy,2011,7(1):2-11.
[10] MATHEW R, KARANTZA-WADSWORTH V, WHITE E. Roleof autophagy in cancer [J]. Nature reviews Cancer,2007,7(12):961-7.
[11] CUERVO A M. Autophagy: in sickness and in health [J]. Trends incell biology,2004,14(2):70-7.
[12] EDINGER A L, THOMPSON C B. Defective autophagy leads tocancer [J]. Cancer cell,2003,4(6):422-4.
[13] CORNILLON S, FOA C, DAVOUST J, et al. Programmed celldeath in Dictyostelium [J]. Journal of cell science,1994,107(Pt10)(2691-704.
[14] HALL D H, GU G, GARCIA-ANOVEROS J, et al.Neuropathology of degenerative cell death in Caenorhabditis elegans [J].The Journal of neuroscience: the official journal of the Society forNeuroscience,1997,17(3):1033-45.
[15] SHEN H M, CODOGNO P. Autophagic cell death: Loch Nessmonster or endangered species?[J]. Autophagy,2011,7(5):457-65.
[16] LEVINE B, YUAN J. Autophagy in cell death: an innocent convict?[J]. The Journal of clinical investigation,2005,115(10):2679-88.
[17] BURSCH W. The autophagosomal-lysosomal compartment inprogrammed cell death [J]. Cell death and differentiation,2001,8(6):569-81.
[18] CLARKE P G. Developmental cell death: morphological diversityand multiple mechanisms [J]. Anatomy and embryology,1990,181(3):195-213.
[19] LOCKSHIN R A, ZAKERI Z. Apoptosis, autophagy, and more [J].The international journal of biochemistry&cell biology,2004,36(12):2405-19.
[20] PATTINGRE S, TASSA A, QU X, et al. Bcl-2antiapoptoticproteins inhibit Beclin1-dependent autophagy [J]. Cell,2005,122(6):927-39.
[21] SCOTT R C, JUHASZ G, NEUFELD T P. Direct induction ofautophagy by Atg1inhibits cell growth and induces apoptotic cell death[J]. Current biology: CB,2007,17(1):1-11.
[22] BERRY D L, BAEHRECKE E H. Growth arrest and autophagy arerequired for salivary gland cell degradation in Drosophila [J]. Cell,2007,131(6):1137-48.
[23] XU Y, KIM S O, LI Y, et al. Autophagy contributes to caspase-independent macrophage cell death [J]. The Journal of biologicalchemistry,2006,281(28):19179-87.
[24] MAIURI M C, ZALCKVAR E, KIMCHI A, et al. Self-eating andself-killing: crosstalk between autophagy and apoptosis [J]. Naturereviews Molecular cell biology,2007,8(9):741-52.
[25] KROEMER G, LEVINE B. Autophagic cell death: the story of amisnomer [J]. Nature reviews Molecular cell biology,2008,9(12):1004-10.
[26] YANG D S, KUMAR A, STAVRIDES P, et al. Neuronal apoptosisand autophagy cross talk in aging PS/APP mice, a model of Alzheimer'sdisease [J]. The American journal of pathology,2008,173(3):665-81.
[27] HARA T, NAKAMURA K, MATSUI M, et al. Suppression ofbasal autophagy in neural cells causes neurodegenerative disease in mice[J]. Nature,2006,441(7095):885-9.
[28] YANG Z J, CHEE C E, HUANG S, et al. The role of autophagy incancer: therapeutic implications [J]. Molecular cancer therapeutics,2011,10(9):1533-41.
[29] QU X, YU J, BHAGAT G, et al. Promotion of tumorigenesis byheterozygous disruption of the beclin1autophagy gene [J]. The Journalof clinical investigation,2003,112(12):1809-20.
[30] FURUYA N, YU J, BYFIELD M, et al. The evolutionarilyconserved domain of Beclin1is required for Vps34binding, autophagyand tumor suppressor function [J]. Autophagy,2005,1(1):46-52.
[31] AITA V M, LIANG X H, MURTY V V, et al. Cloning andgenomic organization of beclin1, a candidate tumor suppressor gene onchromosome17q21[J]. Genomics,1999,59(1):59-65.
[32] MIRACCO C, COSCI E, OLIVERI G, et al. Protein and mRNAexpression of autophagy gene Beclin1in human brain tumours [J].International journal of oncology,2007,30(2):429-36.
[33] SRIDHAR S, BOTBOL Y, MACIAN F, et al. Autophagy anddisease: always two sides to a problem [J]. The Journal of pathology,2012,226(2):255-73.
[34] KONDO Y, KANZAWA T, SAWAYA R, et al. The role ofautophagy in cancer development and response to therapy [J]. Naturereviews Cancer,2005,5(9):726-34.
[35] YANG S, WANG X, CONTINO G, et al. Pancreatic cancersrequire autophagy for tumor growth [J]. Genes&development,2011,25(7):717-29.
[36] GUO J Y, CHEN H Y, MATHEW R, et al. Activated Ras requiresautophagy to maintain oxidative metabolism and tumorigenesis [J]. Genes&development,2011,25(5):460-70.
[37] AREDIA F, GUAMáN ORTIZ L M, GIANSANTI V, et al.Autophagy and Cancer [J]. Cells,2012,1(3):520-34.
[38] FUJITA N, YOSHIMORI T. Ubiquitination-mediated autophagyagainst invading bacteria [J]. Current opinion in cell biology,2011,23(4):492-7.
[39] ESPERT L, CODOGNO P, BIARD-PIECHACZYK M.Involvement of autophagy in viral infections: antiviral function andsubversion by viruses [J]. J Mol Med (Berl),2007,85(8):811-23.
[40] KUDCHODKAR S B, LEVINE B. Viruses and autophagy [J].Reviews in medical virology,2009,19(6):359-78.
[41] MARINO G, MADEO F, KROEMER G. Autophagy for tissuehomeostasis and neuroprotection [J]. Current opinion in cell biology,2011,23(2):198-206.
[42] RAVIKUMAR B, SARKAR S, DAVIES J E, et al. Regulation ofmammalian autophagy in physiology and pathophysiology [J].Physiological reviews,2010,90(4):1383-435.
[43] NARENDRA D, TANAKA A, SUEN D F, et al. Parkin-inducedmitophagy in the pathogenesis of Parkinson disease [J]. Autophagy,2009,5(5):706-8.
[44] YU W H, CUERVO A M, KUMAR A, et al. Macroautophagy--anovel Beta-amyloid peptide-generating pathway activated in Alzheimer'sdisease [J]. The Journal of cell biology,2005,171(1):87-98.
[45] JIA G, CHENG G, GANGAHAR D M, et al. Insulin-like growthfactor-1and TNF-alpha regulate autophagy through c-jun N-terminalkinase and Akt pathways in human atherosclerotic vascular smooth cells[J]. Immunology and cell biology,2006,84(5):448-54.
[46] MARTINET W, KNAAPEN M W, KOCKX M M, et al.Autophagy in cardiovascular disease [J]. Trends in molecular medicine,2007,13(11):482-91.
[47] YANG Z, KLIONSKY D J. An overview of the molecularmechanism of autophagy [J]. Current topics in microbiology andimmunology,2009,335(1-32.
[48] XIE Z, KLIONSKY D J. Autophagosome formation: coremachinery and adaptations [J]. Nature cell biology,2007,9(10):1102-9.
[49] JUNG C H, JUN C B, RO S H, et al. ULK-Atg13-FIP200complexes mediate mTOR signaling to the autophagy machinery [J].Molecular biology of the cell,2009,20(7):1992-2003.
[50] KAMADA Y, FUNAKOSHI T, SHINTANI T, et al. Tor-mediatedinduction of autophagy via an Apg1protein kinase complex [J]. TheJournal of cell biology,2000,150(6):1507-13.
[51] HOSOKAWA N, HARA T, KAIZUKA T, et al. Nutrient-dependent mTORC1association with the ULK1-Atg13-FIP200complexrequired for autophagy [J]. Molecular biology of the cell,2009,20(7):1981-91.
[52] MERCER C A, KALIAPPAN A, DENNIS P B. A novel, humanAtg13binding protein, Atg101, interacts with ULK1and is essential formacroautophagy [J]. Autophagy,2009,5(5):649-62.
[53] KLIONSKY D J, ABELIOVICH H, AGOSTINIS P, et al.Guidelines for the use and interpretation of assays for monitoringautophagy in higher eukaryotes [J]. Autophagy,2008,4(2):151-75.
[54] JUNG C H, SEO M, OTTO N M, et al. ULK1inhibits the kinaseactivity of mTORC1and cell proliferation [J]. Autophagy,2011,7(10):1212-21.
[55] MIZUSHIMA N, NODA T, YOSHIMORI T, et al. A proteinconjugation system essential for autophagy [J]. Nature,1998,395(6700):395-8.
[56] MIZUSHIMA N, KUMA A, KOBAYASHI Y, et al. MouseApg16L, a novel WD-repeat protein, targets to the autophagic isolationmembrane with the Apg12-Apg5conjugate [J]. Journal of cell science,2003,116(Pt9):1679-88.
[57] KUMA A, MIZUSHIMA N, ISHIHARA N, et al. Formation of theapproximately350-kDa Apg12-Apg5.Apg16multimeric complex,mediated by Apg16oligomerization, is essential for autophagy in yeast[J]. The Journal of biological chemistry,2002,277(21):18619-25.
[58] KIRISAKO T, BABA M, ISHIHARA N, et al. Formation processof autophagosome is traced with Apg8/Aut7p in yeast [J]. The Journal ofcell biology,1999,147(2):435-46.
[59] KIRISAKO T, ICHIMURA Y, OKADA H, et al. The reversiblemodification regulates the membrane-binding state of Apg8/Aut7essential for autophagy and the cytoplasm to vacuole targeting pathway[J]. The Journal of cell biology,2000,151(2):263-76.
[60] ICHIMURA Y, KIRISAKO T, TAKAO T, et al. A ubiquitin-likesystem mediates protein lipidation [J]. Nature,2000,408(6811):488-92.
[61] ICHIMURA Y, IMAMURA Y, EMOTO K, et al. In vivo and invitro reconstitution of Atg8conjugation essential for autophagy [J]. TheJournal of biological chemistry,2004,279(39):40584-92.
[62] FUJITA N, ITOH T, OMORI H, et al. The Atg16L complexspecifies the site of LC3lipidation for membrane biogenesis in autophagy[J]. Molecular biology of the cell,2008,19(5):2092-100.
[63] HANADA T, NODA N N, SATOMI Y, et al. The Atg12-Atg5conjugate has a novel E3-like activity for protein lipidation in autophagy[J]. The Journal of biological chemistry,2007,282(52):37298-302.
[64] SOU Y S, WAGURI S, IWATA J, et al. The Atg8conjugationsystem is indispensable for proper development of autophagic isolationmembranes in mice [J]. Molecular biology of the cell,2008,19(11):4762-75.
[65] SEGLEN P O, GORDON P B.3-Methyladenine: specific inhibitorof autophagic/lysosomal protein degradation in isolated rat hepatocytes[J]. Proceedings of the National Academy of Sciences of the UnitedStates of America,1982,79(6):1889-92.
[66] PETIOT A, OGIER-DENIS E, BLOMMAART E F, et al. Distinctclasses of phosphatidylinositol3'-kinases are involved in signalingpathways that control macroautophagy in HT-29cells [J]. The Journal ofbiological chemistry,2000,275(2):992-8.
[67] ITAKURA E, KISHI C, INOUE K, et al. Beclin1forms twodistinct phosphatidylinositol3-kinase complexes with mammalian Atg14and UVRAG [J]. Molecular biology of the cell,2008,19(12):5360-72.
[68] SUN Q, FAN W, CHEN K, et al. Identification of Barkor as amammalian autophagy-specific factor for Beclin1and class IIIphosphatidylinositol3-kinase [J]. Proceedings of the National Academyof Sciences of the United States of America,2008,105(49):19211-6.
[69] LIANG C, FENG P, KU B, et al. Autophagic and tumoursuppressor activity of a novel Beclin1-binding protein UVRAG [J].Nature cell biology,2006,8(7):688-99.
[70] MATSUNAGA K, SAITOH T, TABATA K, et al. Two Beclin1-binding proteins, Atg14L and Rubicon, reciprocally regulate autophagy atdifferent stages [J]. Nature cell biology,2009,11(4):385-96.
[71] ZHONG Y, WANG Q J, LI X, et al. Distinct regulation ofautophagic activity by Atg14L and Rubicon associated with Beclin1-phosphatidylinositol-3-kinase complex [J]. Nature cell biology,2009,11(4):468-76.
[72] BULLER C L, LOBERG R D, FAN M H, et al. A GSK-3/TSC2/mTOR pathway regulates glucose uptake and GLUT1glucosetransporter expression [J]. American journal of physiology Cellphysiology,2008,295(3): C836-43.
[73] TAKAHASHI Y, COPPOLA D, MATSUSHITA N, et al. Bif-1interacts with Beclin1through UVRAG and regulates autophagy andtumorigenesis [J]. Nature cell biology,2007,9(10):1142-51.
[74] TAKAHASHI Y, MEYERKORD C L, WANG H G. Bif-1/endophilin B1: a candidate for crescent driving force in autophagy [J].Cell death and differentiation,2009,16(7):947-55.
[75] LIANG C, LEE J S, INN K S, et al. Beclin1-binding UVRAGtargets the class C Vps complex to coordinate autophagosome maturationand endocytic trafficking [J]. Nature cell biology,2008,10(7):776-87.
[76] FIMIA G M, STOYKOVA A, ROMAGNOLI A, et al. Ambra1regulates autophagy and development of the nervous system [J]. Nature,2007,447(7148):1121-5.
[77] YOUNG A R, CHAN E Y, HU X W, et al. Starvation and ULK1-dependent cycling of mammalian Atg9between the TGN and endosomes[J]. Journal of cell science,2006,119(Pt18):3888-900.
[78] REGGIORI F, TUCKER K A, STROMHAUG P E, et al. TheAtg1-Atg13complex regulates Atg9and Atg23retrieval transport fromthe pre-autophagosomal structure [J]. Developmental cell,2004,6(1):79-90.
[79] ROPOLO A, GRASSO D, PARDO R, et al. The pancreatitis-induced vacuole membrane protein1triggers autophagy in mammaliancells [J]. The Journal of biological chemistry,2007,282(51):37124-33.
[80] NOWAK J, ARCHANGE C, TARDIVEL-LACOMBE J, et al. TheTP53INP2protein is required for autophagy in mammalian cells [J].Molecular biology of the cell,2009,20(3):870-81.
[81] WANG X, PROUD C G. mTORC1signaling: what we still don'tknow [J]. Journal of molecular cell biology,2011,3(4):206-20.
[82] WATANABE R, WEI L, HUANG J. mTOR signaling, function,novel inhibitors, and therapeutic targets [J]. Journal of nuclear medicine:official publication, Society of Nuclear Medicine,2011,52(4):497-500.
[83] SENGUPTA S, PETERSON T R, SABATINI D M. Regulation ofthe mTOR complex1pathway by nutrients, growth factors, and stress [J].Molecular cell,2010,40(2):310-22.
[84] POPULO H, LOPES J M, SOARES P. The mTOR SignallingPathway in Human Cancer [J]. International journal of molecular sciences,2012,13(2):1886-918.
[85] CODOGNO P, MEIJER A J. Autophagy and signaling: their rolein cell survival and cell death [J]. Cell death and differentiation,2005,12Suppl2(1509-18.
[86] SARBASSOV D D, ALI S M, SENGUPTA S, et al. Prolongedrapamycin treatment inhibits mTORC2assembly and Akt/PKB [J].Molecular cell,2006,22(2):159-68.
[87] GUERTIN D A, SABATINI D M. Defining the role of mTOR incancer [J]. Cancer cell,2007,12(1):9-22.
[88] MAGNUSON B, EKIM B, FINGAR D C. Regulation and functionof ribosomal protein S6kinase (S6K) within mTOR signalling networks[J]. The Biochemical journal,2012,441(1):1-21.
[89] BROWN E J, BEAL P A, KEITH C T, et al. Control of p70s6kinase by kinase activity of FRAP in vivo [J]. Nature,1995,377(6548):441-6.
[90] LAWRENCE J C, JR., ABRAHAM R T. PHAS/4E-BPs asregulators of mRNA translation and cell proliferation [J]. Trends inbiochemical sciences,1997,22(9):345-9.
[91] ARICO S, PETIOT A, BAUVY C, et al. The tumor suppressorPTEN positively regulates macroautophagy by inhibiting thephosphatidylinositol3-kinase/protein kinase B pathway [J]. The Journalof biological chemistry,2001,276(38):35243-6.
[92] INOKI K, LI Y, ZHU T, et al. TSC2is phosphorylated andinhibited by Akt and suppresses mTOR signalling [J]. Nature cell biology,2002,4(9):648-57.
[93] MA L, CHEN Z, ERDJUMENT-BROMAGE H, et al.Phosphorylation and functional inactivation of TSC2by Erk implicationsfor tuberous sclerosis and cancer pathogenesis [J]. Cell,2005,121(2):179-93.
[94] HE C, KLIONSKY D J. Regulation mechanisms and signalingpathways of autophagy [J]. Annual review of genetics,2009,43(67-93.
[95] FURUTA S, HIDAKA E, OGATA A, et al. Ras is involved in thenegative control of autophagy through the class I PI3-kinase [J].Oncogene,2004,23(22):3898-904.
[96] PATTINGRE S, BAUVY C, CODOGNO P. Amino acids interferewith the ERK1/2-dependent control of macroautophagy by controlling theactivation of Raf-1in human colon cancer HT-29cells [J]. The Journal ofbiological chemistry,2003,278(19):16667-74.
[97] SARBASSOV D D, GUERTIN D A, ALI S M, et al.Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex[J]. Science,2005,307(5712):1098-101.
[98] MAMMUCARI C, MILAN G, ROMANELLO V, et al. FoxO3controls autophagy in skeletal muscle in vivo [J]. Cell metabolism,2007,6(6):458-71.
[99] GWINN D M, SHACKELFORD D B, EGAN D F, et al. AMPKphosphorylation of raptor mediates a metabolic checkpoint [J]. Molecularcell,2008,30(2):214-26.
[100] LIANG J, SHAO S H, XU Z X, et al. The energy sensing LKB1-AMPK pathway regulates p27(kip1) phosphorylation mediating thedecision to enter autophagy or apoptosis [J]. Nature cell biology,2007,9(2):218-24.
[101] HOYER-HANSEN M, BASTHOLM L, SZYNIAROWSKI P, et al.Control of macroautophagy by calcium, calmodulin-dependent kinasekinase-beta, and Bcl-2[J]. Molecular cell,2007,25(2):193-205.
[102] HERRERO-MARTIN G, HOYER-HANSEN M, GARCIA-GARCIA C, et al. TAK1activates AMPK-dependent cytoprotectiveautophagy in TRAIL-treated epithelial cells [J]. The EMBO journal,2009,28(6):677-85.
[103] PAPANDREOU I, LIM A L, LADEROUTE K, et al. Hypoxiasignals autophagy in tumor cells via AMPK activity, independent of HIF-1, BNIP3, and BNIP3L [J]. Cell death and differentiation,2008,15(10):1572-81.
[104] LEVINE B, ABRAMS J. p53: The Janus of autophagy?[J]. Naturecell biology,2008,10(6):637-9.
[105] FENG Z, ZHANG H, LEVINE A J, et al. The coordinateregulation of the p53and mTOR pathways in cells [J]. Proceedings of theNational Academy of Sciences of the United States of America,2005,102(23):8204-9.
[106] CRIGHTON D, WILKINSON S, O'PREY J, et al. DRAM, a p53-induced modulator of autophagy, is critical for apoptosis [J]. Cell,2006,126(1):121-34.
[107] TASDEMIR E, MAIURI M C, GALLUZZI L, et al. Regulation ofautophagy by cytoplasmic p53[J]. Nature cell biology,2008,10(6):676-87.
[108] MORSELLI E, TASDEMIR E, MAIURI M C, et al. Mutant p53protein localized in the cytoplasm inhibits autophagy [J]. Cell Cycle,2008,7(19):3056-61.
[109] SUI X, JIN L, HUANG X, et al. p53signaling and autophagy incancer: a revolutionary strategy could be developed for cancer treatment[J]. Autophagy,2011,7(6):565-71.
[110] LEVINE B, SINHA S, KROEMER G. Bcl-2family members: dualregulators of apoptosis and autophagy [J]. Autophagy,2008,4(5):600-6.
[111] MAIURI M C, LE TOUMELIN G, CRIOLLO A, et al. Functionaland physical interaction between Bcl-X(L) and a BH3-like domain inBeclin-1[J]. The EMBO journal,2007,26(10):2527-39.
[112] WEI Y, PATTINGRE S, SINHA S, et al. JNK1-mediatedphosphorylation of Bcl-2regulates starvation-induced autophagy [J].Molecular cell,2008,30(6):678-88.
[113] ZALCKVAR E, BERISSI H, MIZRACHY L, et al. DAP-kinase-mediated phosphorylation on the BH3domain of beclin1promotesdissociation of beclin1from Bcl-XL and induction of autophagy [J].EMBO reports,2009,10(3):285-92.
[114] KASTAN M B, LIM D S. The many substrates and functions ofATM [J]. Nature reviews Molecular cell biology,2000,1(3):179-86.
[115] LAVIN M F, SHILOH Y. The genetic defect in ataxia-telangiectasia [J]. Annual review of immunology,1997,15(177-202.
[116] SAVITSKY K, SFEZ S, TAGLE D A, et al. The completesequence of the coding region of the ATM gene reveals similarity to cellcycle regulators in different species [J]. Human molecular genetics,1995,4(11):2025-32.
[117] GATTI R A, BERKEL I, BODER E, et al. Localization of anataxia-telangiectasia gene to chromosome11q22-23[J]. Nature,1988,336(6199):577-80.
[118] ABRAHAM R T. PI3-kinase related kinases:'big' players instress-induced signaling pathways [J]. DNA repair,2004,3(8-9):883-7.
[119] BAKKENIST C J, KASTAN M B. DNA damage activates ATMthrough intermolecular autophosphorylation and dimer dissociation [J].Nature,2003,421(6922):499-506.
[120] ANDEGEKO Y, MOYAL L, MITTELMAN L, et al. Nuclearretention of ATM at sites of DNA double strand breaks [J]. The Journalof biological chemistry,2001,276(41):38224-30.
[121] D'AMOURS D, JACKSON S P. The Mre11complex: at thecrossroads of dna repair and checkpoint signalling [J]. Nature reviewsMolecular cell biology,2002,3(5):317-27.
[122] UZIEL T, LERENTHAL Y, MOYAL L, et al. Requirement of theMRN complex for ATM activation by DNA damage [J]. The EMBOjournal,2003,22(20):5612-21.
[123] LAVIN M F. The Mre11complex and ATM: a two-way functionalinteraction in recognising and signaling DNA double strand breaks [J].DNA repair,2004,3(11):1515-20.
[124] LEE J H, PAULL T T. ATM activation by DNA double-strandbreaks through the Mre11-Rad50-Nbs1complex [J]. Science,2005,308(5721):551-4.
[125] KITAGAWA R, BAKKENIST C J, MCKINNON P J, et al.Phosphorylation of SMC1is a critical downstream event in the ATM-NBS1-BRCA1pathway [J]. Genes&development,2004,18(12):1423-38.
[126] PETRINI J H, STRACKER T H. The cellular response to DNAdouble-strand breaks: defining the sensors and mediators [J]. Trends incell biology,2003,13(9):458-62.
[127] SHILOH Y. ATM and related protein kinases: safeguardinggenome integrity [J]. Nature reviews Cancer,2003,3(3):155-68.
[128] POLO S E, JACKSON S P. Dynamics of DNA damage responseproteins at DNA breaks: a focus on protein modifications [J]. Genes&development,2011,25(5):409-33.
[129] KASTAN M B, ONYEKWERE O, SIDRANSKY D, et al.Participation of p53protein in the cellular response to DNA damage [J].Cancer research,1991,51(23Pt1):6304-11.
[130] CANMAN C E, LIM D S, CIMPRICH K A, et al. Activation of theATM kinase by ionizing radiation and phosphorylation of p53[J].Science,1998,281(5383):1677-9.
[131] LIM D S, KIM S T, XU B, et al. ATM phosphorylates p95/nbs1inan S-phase checkpoint pathway [J]. Nature,2000,404(6778):613-7.
[132] XU B, O'DONNELL A H, KIM S T, et al. Phosphorylation ofserine1387in Brca1is specifically required for the Atm-mediated S-phase checkpoint after ionizing irradiation [J]. Cancer research,2002,62(16):4588-91.
[133] KASTAN M B, BARTEK J. Cell-cycle checkpoints and cancer [J].Nature,2004,432(7015):316-23.
[134] LUKAS J, LUKAS C, BARTEK J. Mammalian cell cyclecheckpoints: signalling pathways and their organization in space and time[J]. DNA repair,2004,3(8-9):997-1007.
[135] BAO S, TIBBETTS R S, BRUMBAUGH K M, et al. ATR/ATM-mediated phosphorylation of human Rad17is required for genotoxicstress responses [J]. Nature,2001,411(6840):969-74.
[136] SAPKOTA G P, DEAK M, KIELOCH A, et al. Ionizing radiationinduces ataxia telangiectasia mutated kinase (ATM)-mediatedphosphorylation of LKB1/STK11at Thr-366[J]. The Biochemicaljournal,2002,368(Pt2):507-16.
[137] ALEXANDER A, WALKER C L. The role of LKB1and AMPKin cellular responses to stress and damage [J]. FEBS letters,2011,585(7):952-7.
[138] ALEXANDER A, CAI S L, KIM J, et al. ATM signals to TSC2inthe cytoplasm to regulate mTORC1in response to ROS [J]. Proceedingsof the National Academy of Sciences of the United States of America,2010,107(9):4153-8.
[139] MENENDEZ J A, CUFI S, OLIVERAS-FERRAROS C, et al.Metformin and the ATM DNA damage response (DDR): accelerating theonset of stress-induced senescence to boost protection against cancer [J].Aging,2011,3(11):1063-77.
[140] BUDANOV A V, KARIN M. p53target genes sestrin1andsestrin2connect genotoxic stress and mTOR signaling [J]. Cell,2008,134(3):451-60.
[141] DUAN X, PONOMAREVA L, VEERANKI S, et al. IFI16induction by glucose restriction in human fibroblasts contributes toautophagy through activation of the ATM/AMPK/p53pathway [J]. PloSone,2011,6(5): e19532.
[142] ZHOU W J, DENG R, ZHANG X Y, et al. G-quadruplex ligandSYUIQ-5induces autophagy by telomere damage and TRF2delocalization in cancer cells [J]. Molecular cancer therapeutics,2009,8(12):3203-13.
[143] CHEN L H, LOONG C C, SU T L, et al. Autophagy inhibitionenhances apoptosis triggered by BO-1051, an N-mustard derivative, andinvolves the ATM signaling pathway [J]. Biochemical pharmacology,2011,81(5):594-605.
[144] SINGH K, MATSUYAMA S, DRAZBA J A, et al. Autophagy-dependent senescence in response to DNA damage and chronic apoptoticstress [J]. Autophagy,2012,8(2):236-51.
[145] BRICHKINA A, BULAVIN D V. WIP-ing out atherosclerosiswith autophagy [J]. Autophagy,2012,8(10):1545-7.
[146] LE GUEZENNEC X, BRICHKINA A, HUANG Y F, et al. Wip1-dependent regulation of autophagy, obesity, and atherosclerosis [J]. Cellmetabolism,2012,16(1):68-80.
[147] ZHOU K, BELLENGUEZ C, SPENCER C C, et al. Commonvariants near ATM are associated with glycemic response to metformin intype2diabetes [J]. Nature genetics,2011,43(2):117-20.
[148] LEE R, FEINBAUM R, AMBROS V. A short history of a shortRNA [J]. Cell,2004,116(2Suppl): S89-92,1p following S6.
[149] RUVKUN G, WIGHTMAN B, HA I. The20years it took torecognize the importance of tiny RNAs [J]. Cell,2004,116(2Suppl):S93-6,2p following S6.
[150] REINHART B J, SLACK F J, BASSON M, et al. The21-nucleotide let-7RNA regulates developmental timing in Caenorhabditiselegans [J]. Nature,2000,403(6772):901-6.
[151] GRIFFITHS-JONES S. The microRNA Registry [J]. Nucleic acidsresearch,2004,32(Database issue): D109-11.
[152] FRIEDMAN R C, FARH K K, BURGE C B, et al. Mostmammalian mRNAs are conserved targets of microRNAs [J]. Genomeresearch,2009,19(1):92-105.
[153] SELBACH M, SCHWANHAUSSER B, THIERFELDER N, et al.Widespread changes in protein synthesis induced by microRNAs [J].Nature,2008,455(7209):58-63.
[154] SAINI H K, GRIFFITHS-JONES S, ENRIGHT A J. Genomicanalysis of human microRNA transcripts [J]. Proceedings of the NationalAcademy of Sciences of the United States of America,2007,104(45):17719-24.
[155] RODRIGUEZ A, GRIFFITHS-JONES S, ASHURST J L, et al.Identification of mammalian microRNA host genes and transcriptionunits [J]. Genome research,2004,14(10A):1902-10.
[156] KIM V N. MicroRNA biogenesis: coordinated cropping and dicing[J]. Nature reviews Molecular cell biology,2005,6(5):376-85.
[157] LEE Y, KIM M, HAN J, et al. MicroRNA genes are transcribed byRNA polymerase II [J]. The EMBO journal,2004,23(20):4051-60.
[158] BORCHERT G M, LANIER W, DAVIDSON B L. RNApolymerase III transcribes human microRNAs [J]. Nature structural&molecular biology,2006,13(12):1097-101.
[159] DENLI A M, TOPS B B, PLASTERK R H, et al. Processing ofprimary microRNAs by the Microprocessor complex [J]. Nature,2004,432(7014):231-5.
[160] HAN J, LEE Y, YEOM K H, et al. Molecular basis for therecognition of primary microRNAs by the Drosha-DGCR8complex [J].Cell,2006,125(5):887-901.
[161] LUND E, GUTTINGER S, CALADO A, et al. Nuclear export ofmicroRNA precursors [J]. Science,2004,303(5654):95-8.
[162] BOHNSACK M T, CZAPLINSKI K, GORLICH D. Exportin5is aRanGTP-dependent dsRNA-binding protein that mediates nuclear exportof pre-miRNAs [J]. RNA,2004,10(2):185-91.
[163] HUTVAGNER G, MCLACHLAN J, PASQUINELLI A E, et al. Acellular function for the RNA-interference enzyme Dicer in thematuration of the let-7small temporal RNA [J]. Science,2001,293(5531):834-8.
[164] GREGORY R I, CHENDRIMADA T P, COOCH N, et al. HumanRISC couples microRNA biogenesis and posttranscriptional genesilencing [J]. Cell,2005,123(4):631-40.
[165] MACRAE I J, DOUDNA J A. Ribonuclease revisited: structuralinsights into ribonuclease III family enzymes [J]. Current opinion instructural biology,2007,17(1):138-45.
[166] MACRAE I J, ZHOU K, DOUDNA J A. Structural determinantsof RNA recognition and cleavage by Dicer [J]. Nature structural&molecular biology,2007,14(10):934-40.
[167] MACRAE I J, ZHOU K, LI F, et al. Structural basis for double-stranded RNA processing by Dicer [J]. Science,2006,311(5758):195-8.
[168] CHENDRIMADA T P, GREGORY R I, KUMARASWAMY E, etal. TRBP recruits the Dicer complex to Ago2for microRNA processingand gene silencing [J]. Nature,2005,436(7051):740-4.
[169] LEE Y, HUR I, PARK S Y, et al. The role of PACT in the RNAsilencing pathway [J]. The EMBO journal,2006,25(3):522-32.
[170] HUTVAGNER G, SIMARD M J. Argonaute proteins: key playersin RNA silencing [J]. Nature reviews Molecular cell biology,2008,9(1):22-32.
[171] SETO A G, KINGSTON R E, LAU N C. The coming of age forPiwi proteins [J]. Molecular cell,2007,26(5):603-9.
[172] HUTVAGNER G. Small RNA asymmetry in RNAi: function inRISC assembly and gene regulation [J]. FEBS letters,2005,579(26):5850-7.
[173] RO S, PARK C, YOUNG D, et al. Tissue-dependent pairedexpression of miRNAs [J]. Nucleic acids research,2007,35(17):5944-53.
[174] BASKERVILLE S, BARTEL D P. Microarray profiling ofmicroRNAs reveals frequent coexpression with neighboring miRNAs andhost genes [J]. RNA,2005,11(3):241-7.
[175] SONG G, WANG L. MiR-433and miR-127arise fromindependent overlapping primary transcripts encoded by the miR-433-127locus [J]. PloS one,2008,3(10): e3574.
[176] SEMPERE L F, FREEMANTLE S, PITHA-ROWE I, et al.Expression profiling of mammalian microRNAs uncovers a subset ofbrain-expressed microRNAs with possible roles in murine and humanneuronal differentiation [J]. Genome biology,2004,5(3): R13.
[177] GUIL S, CACERES J F. The multifunctional RNA-binding proteinhnRNP A1is required for processing of miR-18a [J]. Nature structural&molecular biology,2007,14(7):591-6.
[178] MEYER N, PENN L Z. Reflecting on25years with MYC [J].Nature reviews Cancer,2008,8(12):976-90.
[179] O'DONNELL K A, WENTZEL E A, ZELLER K I, et al. c-Myc-regulated microRNAs modulate E2F1expression [J]. Nature,2005,435(7043):839-43.
[180] CHANG T C, YU D, LEE Y S, et al. Widespread microRNArepression by Myc contributes to tumorigenesis [J]. Nature genetics,2008,40(1):43-50.
[181] RAVER-SHAPIRA N, MARCIANO E, MEIRI E, et al.Transcriptional activation of miR-34a contributes to p53-mediatedapoptosis [J]. Molecular cell,2007,26(5):731-43.
[182] BARTEL D P. MicroRNAs: genomics, biogenesis, mechanism,and function [J]. Cell,2004,116(2):281-97.
[183] BRENNECKE J, STARK A, RUSSELL R B, et al. Principles ofmicroRNA-target recognition [J]. PLoS biology,2005,3(3): e85.
[184] BRODERSEN P, VOINNET O. Revisiting the principles ofmicroRNA target recognition and mode of action [J]. Nature reviewsMolecular cell biology,2009,10(2):141-8.
[185] MERRICK W C. Cap-dependent and cap-independent translationin eukaryotic systems [J]. Gene,2004,332(1-11.
[186] DERRY M C, YANAGIYA A, MARTINEAU Y, et al. Regulationof poly(A)-binding protein through PABP-interacting proteins [J]. ColdSpring Harbor symposia on quantitative biology,2006,71(537-43.
[187] JACKSON R J. Alternative mechanisms of initiating translation ofmammalian mRNAs [J]. Biochemical Society transactions,2005,33(Pt6):1231-41.
[188] PILLAI R S, BHATTACHARYYA S N, ARTUS C G, et al.Inhibition of translational initiation by Let-7MicroRNA in human cells[J]. Science,2005,309(5740):1573-6.
[189] HUMPHREYS D T, WESTMAN B J, MARTIN D I, et al.MicroRNAs control translation initiation by inhibiting eukaryoticinitiation factor4E/cap and poly(A) tail function [J]. Proceedings of theNational Academy of Sciences of the United States of America,2005,102(47):16961-6.
[190] CHO P F, POULIN F, CHO-PARK Y A, et al. A new paradigm fortranslational control: inhibition via5'-3' mRNA tethering by Bicoid andthe eIF4E cognate4EHP [J]. Cell,2005,121(3):411-23.
[191] RICHTER J D, SONENBERG N. Regulation of cap-dependenttranslation by eIF4E inhibitory proteins [J]. Nature,2005,433(7025):477-80.
[192] KIRIAKIDOU M, TAN G S, LAMPRINAKI S, et al. An mRNAm7G cap binding-like motif within human Ago2represses translation [J].Cell,2007,129(6):1141-51.
[193] WAKIYAMA M, TAKIMOTO K, OHARA O, et al. Let-7microRNA-mediated mRNA deadenylation and translational repressionin a mammalian cell-free system [J]. Genes&development,2007,21(15):1857-62.
[194] WANG B, LOVE T M, CALL M E, et al. Recapitulation of shortRNA-directed translational gene silencing in vitro [J]. Molecular cell,2006,22(4):553-60.
[195] CHENDRIMADA T P, FINN K J, JI X, et al. MicroRNA silencingthrough RISC recruitment of eIF6[J]. Nature,2007,447(7146):823-8.
[196] BASU U, SI K, WARNER J R, et al. The Saccharomycescerevisiae TIF6gene encoding translation initiation factor6is requiredfor60S ribosomal subunit biogenesis [J]. Molecular and cellular biology,2001,21(5):1453-62.
[197] OLSEN P H, AMBROS V. The lin-4regulatory RNA controlsdevelopmental timing in Caenorhabditis elegans by blocking LIN-14protein synthesis after the initiation of translation [J]. Developmentalbiology,1999,216(2):671-80.
[198] SEGGERSON K, TANG L, MOSS E G. Two genetic circuitsrepress the Caenorhabditis elegans heterochronic gene lin-28aftertranslation initiation [J]. Developmental biology,2002,243(2):215-25.
[199] PETERSEN C P, BORDELEAU M E, PELLETIER J, et al. ShortRNAs repress translation after initiation in mammalian cells [J].Molecular cell,2006,21(4):533-42.
[200] NOTTROTT S, SIMARD M J, RICHTER J D. Human let-7amiRNA blocks protein production on actively translating polyribosomes[J]. Nature structural&molecular biology,2006,13(12):1108-14.
[201] WU L, FAN J, BELASCO J G. MicroRNAs direct rapiddeadenylation of mRNA [J]. Proceedings of the National Academy ofSciences of the United States of America,2006,103(11):4034-9.
[202] LIM L P, LAU N C, GARRETT-ENGELE P, et al. Microarrayanalysis shows that some microRNAs downregulate large numbers oftarget mRNAs [J]. Nature,2005,433(7027):769-73.
[203] BAGGA S, BRACHT J, HUNTER S, et al. Regulation by let-7andlin-4miRNAs results in target mRNA degradation [J]. Cell,2005,122(4):553-63.
[204] PARKER R, SONG H. The enzymes and control of eukaryoticmRNA turnover [J]. Nature structural&molecular biology,2004,11(2):121-7.
[205] BEHM-ANSMANT I, REHWINKEL J, DOERKS T, et al. mRNAdegradation by miRNAs and GW182requires both CCR4:NOTdeadenylase and DCP1:DCP2decapping complexes [J]. Genes&development,2006,20(14):1885-98.
[206] GIRALDEZ A J, MISHIMA Y, RIHEL J, et al. Zebrafish MiR-430promotes deadenylation and clearance of maternal mRNAs [J]. Science,2006,312(5770):75-9.
[207] MEISTER G, LANDTHALER M, PATKANIOWSKA A, et al.Human Argonaute2mediates RNA cleavage targeted by miRNAs andsiRNAs [J]. Molecular cell,2004,15(2):185-97.
[208] EULALIO A, BEHM-ANSMANT I, IZAURRALDE E. P bodies:at the crossroads of post-transcriptional pathways [J]. Nature reviewsMolecular cell biology,2007,8(1):9-22.
[209] LIU J, VALENCIA-SANCHEZ M A, HANNON G J, et al.MicroRNA-dependent localization of targeted mRNAs to mammalian P-bodies [J]. Nature cell biology,2005,7(7):719-23.
[210] SEN G L, BLAU H M. Argonaute2/RISC resides in sites ofmammalian mRNA decay known as cytoplasmic bodies [J]. Nature cellbiology,2005,7(6):633-6.
[211] EYSTATHIOY T, CHAN E K, TENENBAUM S A, et al. Aphosphorylated cytoplasmic autoantigen, GW182, associates with aunique population of human mRNAs within novel cytoplasmic speckles[J]. Molecular biology of the cell,2002,13(4):1338-51.
[212] JAKYMIW A, LIAN S, EYSTATHIOY T, et al. Disruption of GWbodies impairs mammalian RNA interference [J]. Nature cell biology,2005,7(12):1267-74.
[213] LIU J, RIVAS F V, WOHLSCHLEGEL J, et al. A role for the P-body component GW182in microRNA function [J]. Nature cell biology,2005,7(12):1261-6.
[214] PAULEY K M, EYSTATHIOY T, JAKYMIW A, et al. Formationof GW bodies is a consequence of microRNA genesis [J]. EMBO reports,2006,7(9):904-10.
[215] CHAN S P, SLACK F J. microRNA-mediated silencing inside P-bodies [J]. RNA biology,2006,3(3):97-100.
[216] VALENCIA-SANCHEZ M A, LIU J, HANNON G J, et al.Control of translation and mRNA degradation by miRNAs and siRNAs[J]. Genes&development,2006,20(5):515-24.
[217] BHATTACHARYYA S N, HABERMACHER R, MARTINE U, etal. Relief of microRNA-mediated translational repression in human cellssubjected to stress [J]. Cell,2006,125(6):1111-24.
[218] MACFARLANE L A, MURPHY P R. MicroRNA: Biogenesis,Function and Role in Cancer [J]. Current genomics,2010,11(7):537-61.
[219] IVEY K N, SRIVASTAVA D. MicroRNAs as regulators ofdifferentiation and cell fate decisions [J]. Cell stem cell,2010,7(1):36-41.
[220] WIENHOLDS E, PLASTERK R H. MicroRNA function in animaldevelopment [J]. FEBS letters,2005,579(26):5911-22.
[221] O'CONNELL R M, RAO D S, CHAUDHURI A A, et al.Physiological and pathological roles for microRNAs in the immunesystem [J]. Nature reviews Immunology,2010,10(2):111-22.
[222] SUAREZ Y, SESSA W C. MicroRNAs as novel regulators ofangiogenesis [J]. Circulation research,2009,104(4):442-54.
[223] WANG Y, LEE C G. MicroRNA and cancer--focus on apoptosis[J]. Journal of cellular and molecular medicine,2009,13(1):12-23.
[224] LI Y, KOWDLEY K V. MicroRNAs in Common Human Diseases[J]. Genomics, proteomics&bioinformatics,2012,10(5):246-53.
[225] LIMA R T, BUSACCA S, ALMEIDA G M, et al. MicroRNAregulation of core apoptosis pathways in cancer [J]. Eur J Cancer,2011,47(2):163-74.
[226] ZHANG B, PAN X, COBB G P, et al. microRNAs as oncogenesand tumor suppressors [J]. Developmental biology,2007,302(1):1-12.
[227] JIANG Q, WANG Y, HAO Y, et al. miR2Disease: a manuallycurated database for microRNA deregulation in human disease [J].Nucleic acids research,2009,37(Database issue): D98-104.
[228] HRASOVEC S, GLAVAC D. MicroRNAs as Novel Biomarkers inColorectal Cancer [J]. Frontiers in genetics,2012,3(180.
[229] HUANG Z, HUANG D, NI S, et al. Plasma microRNAs arepromising novel biomarkers for early detection of colorectal cancer [J].International journal of cancer Journal international du cancer,2010,127(1):118-26.
[230] NG E K, CHONG W W, JIN H, et al. Differential expression ofmicroRNAs in plasma of patients with colorectal cancer: a potentialmarker for colorectal cancer screening [J]. Gut,2009,58(10):1375-81.
[231] AHMED F E, JEFFRIES C D, VOS P W, et al. DiagnosticmicroRNA markers for screening sporadic human colon cancer and activeulcerative colitis in stool and tissue [J]. Cancer genomics&proteomics,2009,6(5):281-95.
[232] SLABY O, SVOBODA M, FABIAN P, et al. Altered expression ofmiR-21, miR-31, miR-143and miR-145is related to clinicopathologicfeatures of colorectal cancer [J]. Oncology,2007,72(5-6):397-402.
[233] SCHETTER A J, LEUNG S Y, SOHN J J, et al. MicroRNAexpression profiles associated with prognosis and therapeutic outcome incolon adenocarcinoma [J]. JAMA: the journal of the American MedicalAssociation,2008,299(4):425-36.
[234] KULDA V, PESTA M, TOPOLCAN O, et al. Relevance of miR-21and miR-143expression in tissue samples of colorectal carcinoma andits liver metastases [J]. Cancer genetics and cytogenetics,2010,200(2):154-60.
[235] IBRAHIM A F, WEIRAUCH U, THOMAS M, et al. MicroRNAreplacement therapy for miR-145and miR-33a is efficacious in a modelof colon carcinoma [J]. Cancer research,2011,71(15):5214-24.
[236] ASLAM M I, PATEL M, SINGH B, et al. MicroRNAmanipulation in colorectal cancer cells: from laboratory to clinicalapplication [J]. Journal of translational medicine,2012,10(128.
[237] WANG P, ZOU F, ZHANG X, et al. microRNA-21negativelyregulates Cdc25A and cell cycle progression in colon cancer cells [J].Cancer research,2009,69(20):8157-65.
[238] WU H, WANG F, HU S, et al. MiR-20a and miR-106b negativelyregulate autophagy induced by leucine deprivation via suppression ofULK1expression in C2C12myoblasts [J]. Cellular signalling,2012,24(11):2179-86.
[239] FU L L, WEN X, BAO J K, et al. MicroRNA-modulatedautophagic signaling networks in cancer [J]. The international journal ofbiochemistry&cell biology,2012,44(5):733-6.
[240] WANG Y X, ZHANG X Y, ZHANG B F, et al. Initial study ofmicroRNA expression profiles of colonic cancer without lymph nodemetastasis [J]. Journal of digestive diseases,2010,11(1):50-4.
[241] DIOSDADO B, VAN DE WIEL M A, TERHAAR SIVE DROSTEJ S, et al. MiR-17-92cluster is associated with13q gain and c-mycexpression during colorectal adenoma to adenocarcinoma progression [J].British journal of cancer,2009,101(4):707-14.
[242] FANG Z M, LEE C S, SARRIS M, et al. Rapid radiation-inductionof ATM protein levels in situ [J]. Pathology,2001,33(1):30-6.
[243] MIZUSHIMA N. Methods for monitoring autophagy using GFP-LC3transgenic mice [J]. Methods in enzymology,2009,452(13-23.
[244] BJORKOY G, LAMARK T, BRECH A, et al. p62/SQSTM1formsprotein aggregates degraded by autophagy and has a protective effect onhuntingtin-induced cell death [J]. The Journal of cell biology,2005,171(4):603-14.
[245] MIZUSHIMA N, YOSHIMORI T, LEVINE B. Methods inmammalian autophagy research [J]. Cell,2010,140(3):313-26.
[246] KHANNA K K, LAVIN M F, JACKSON S P, et al. ATM, acentral controller of cellular responses to DNA damage [J]. Cell deathand differentiation,2001,8(11):1052-65.
[247] DELIA D, FONTANELLA E, FERRARIO C, et al. DNA damage-induced cell-cycle phase regulation of p53and p21waf1in normal andATM-defective cells [J]. Oncogene,2003,22(49):7866-9.
[248] GAUL L, MANDL-WEBER S, BAUMANN P, et al.Bendamustine induces G2cell cycle arrest and apoptosis in myelomacells: the role of ATM-Chk2-Cdc25A and ATM-p53-p21-pathways [J].Journal of cancer research and clinical oncology,2008,134(2):245-53.
[249] HICKSON I, ZHAO Y, RICHARDSON C J, et al. Identificationand characterization of a novel and specific inhibitor of the ataxia-telangiectasia mutated kinase ATM [J]. Cancer research,2004,64(24):9152-9.
[250] GOLDING S E, ROSENBERG E, VALERIE N, et al. ImprovedATM kinase inhibitor KU-60019radiosensitizes glioma cells,compromises insulin, AKT and ERK prosurvival signaling, and inhibitsmigration and invasion [J]. Molecular cancer therapeutics,2009,8(10):2894-902.
[251] RAINEY M D, CHARLTON M E, STANTON R V, et al.Transient inhibition of ATM kinase is sufficient to enhance cellularsensitivity to ionizing radiation [J]. Cancer research,2008,68(18):7466-74.
[252] RIPOLLES L, ORTEGA M, ORTUNO F, et al. Geneticabnormalities and clinical outcome in chronic lymphocytic leukemia [J].Cancer genetics and cytogenetics,2006,171(1):57-64.
[253] AUSTEN B, SKOWRONSKA A, BAKER C, et al. Mutation statusof the residual ATM allele is an important determinant of the cellularresponse to chemotherapy and survival in patients with chroniclymphocytic leukemia containing an11q deletion [J]. Journal of clinicaloncology: official journal of the American Society of Clinical Oncology,2007,25(34):5448-57.
[254] KHALIL H, TUMMALA H, CHAKAROV S, et al. TargetingATM pathway for therapeutic intervention in cancer [J]. Biodiscovery,2012,1(3.
[255] ROGOFF H A, PICKERING M T, FRAME F M, et al. Apoptosisassociated with deregulated E2F activity is dependent on E2F1andAtm/Nbs1/Chk2[J]. Molecular and cellular biology,2004,24(7):2968-77.
[256] WESTPHAL C H, ROWAN S, SCHMALTZ C, et al. atm and p53cooperate in apoptosis and suppression of tumorigenesis, but not inresistance to acute radiation toxicity [J]. Nature genetics,1997,16(4):397-401.
[257] MAYA R, BALASS M, KIM S T, et al. ATM-dependentphosphorylation of Mdm2on serine395: role in p53activation by DNAdamage [J]. Genes&development,2001,15(9):1067-77.
[258] BASKARAN R, WOOD L D, WHITAKER L L, et al. Ataxiatelangiectasia mutant protein activates c-Abl tyrosine kinase in responseto ionizing radiation [J]. Nature,1997,387(6632):516-9.
[259] WANG J Y. Regulation of cell death by the Abl tyrosine kinase [J].Oncogene,2000,19(49):5643-50.
[260] TRUONG T, SUN G, DOORLY M, et al. Modulation of DNAdamage-induced apoptosis by cell adhesion is independently mediated byp53and c-Abl [J]. Proceedings of the National Academy of Sciences ofthe United States of America,2003,100(18):10281-6.
[261] LOWE S W, SCHMITT E M, SMITH S W, et al. p53is requiredfor radiation-induced apoptosis in mouse thymocytes [J]. Nature,1993,362(6423):847-9.
[262] SAITO S, GOODARZI A A, HIGASHIMOTO Y, et al. ATMmediates phosphorylation at multiple p53sites, including Ser(46), inresponse to ionizing radiation [J]. The Journal of biological chemistry,2002,277(15):12491-4.
[263] HIRAO A, KONG Y Y, MATSUOKA S, et al. DNA damage-induced activation of p53by the checkpoint kinase Chk2[J]. Science,2000,287(5459):1824-7.
[264] BORGES H L, CHAO C, XU Y, et al. Radiation-induced apoptosisin developing mouse retina exhibits dose-dependent requirement forATM phosphorylation of p53[J]. Cell death and differentiation,2004,11(5):494-502.
[265] KARLSEDER J, BROCCOLI D, DAI Y, et al. p53-and ATM-dependent apoptosis induced by telomeres lacking TRF2[J]. Science,1999,283(5406):1321-5.
[266] HERZOG K H, CHONG M J, KAPSETAKI M, et al. Requirementfor Atm in ionizing radiation-induced cell death in the developing centralnervous system [J]. Science,1998,280(5366):1089-91.
[267] CHUNG Y M, PARK S H, TSAI W B, et al. FOXO3signallinglinks ATM to the p53apoptotic pathway following DNA damage [J].Nature communications,2012,3(1000.
[268] POWERS J T, HONG S, MAYHEW C N, et al. E2F1uses theATM signaling pathway to induce p53and Chk2phosphorylation andapoptosis [J]. Molecular cancer research: MCR,2004,2(4):203-14.
[269] LUO L, HUANG W, TAO R, et al. ATM and LKB1dependentactivation of AMPK sensitizes cancer cells to etoposide-inducedapoptosis [J]. Cancer letters,2012,
[270] JIANG H, REINHARDT H C, BARTKOVA J, et al. Thecombined status of ATM and p53link tumor development withtherapeutic response [J]. Genes&development,2009,23(16):1895-909.
[271] LI W, DU B, WANG T, et al. Kaempferol induces apoptosis inhuman HCT116colon cancer cells via the Ataxia-TelangiectasiaMutated-p53pathway with the involvement of p53UpregulatedModulator of Apoptosis [J]. Chemico-biological interactions,2009,177(2):121-7.
[272] LAN Y H, CHIANG J H, HUANG W W, et al. Activations of BothExtrinsic and Intrinsic Pathways in HCT116Human Colorectal CancerCells Contribute to Apoptosis through p53-Mediated ATM/Fas Signalingby Emilia sonchifolia Extract, a Folklore Medicinal Plant [J]. Evidence-based complementary and alternative medicine: eCAM,2012,2012(178178.
[273] GUERRA L, ALBIHN A, TRONNERSJO S, et al. Myc is requiredfor activation of the ATM-dependent checkpoints in response to DNAdamage [J]. PloS one,2010,5(1): e8924.
[274] MERTENS F, JOHANSSON B, MITELMAN F. Isochromosomesin neoplasia [J]. Genes, chromosomes&cancer,1994,10(4):221-30.
[275] WANG J, SU F, SMILENOV L B, et al. Mechanisms of increasedrisk of tumorigenesis in Atm and Brca1double heterozygosity [J]. RadiatOncol,2011,6(96.
[276] SHILOH Y. ATM and ATR: networking cellular responses toDNA damage [J]. Current opinion in genetics&development,2001,11(1):71-7.
[277] PROKOPCOVA J, KLEIBL Z, BANWELL C M, et al. The role ofATM in breast cancer development [J]. Breast cancer research andtreatment,2007,104(2):121-8.
[278] GAO Y, HAYES R B, HUANG W Y, et al. DNA repair genepolymorphisms and tobacco smoking in the risk for colorectal adenomas[J]. Carcinogenesis,2011,32(6):882-7.
[279] ROBERTS N J, JIAO Y, YU J, et al. ATM mutations in patientswith hereditary pancreatic cancer [J]. Cancer discovery,2012,2(1):41-6.
[280] THORSTENSON Y R, ROXAS A, KROISS R, et al.Contributions of ATM mutations to familial breast and ovarian cancer [J].Cancer research,2003,63(12):3325-33.
[281] BRENNAN K, GARCIA-CLOSAS M, ORR N, et al. IntragenicATM methylation in peripheral blood DNA as a biomarker of breastcancer risk [J]. Cancer research,2012,72(9):2304-13.
[282] LI M, FANG X, BAKER D J, et al. The ATM-p53pathwaysuppresses aneuploidy-induced tumorigenesis [J]. Proceedings of theNational Academy of Sciences of the United States of America,2010,107(32):14188-93.
[283] BARTKOVA J, HOREJSI Z, KOED K, et al. DNA damageresponse as a candidate anti-cancer barrier in early human tumorigenesis[J]. Nature,2005,434(7035):864-70.
[284] GORGOULIS V G, VASSILIOU L V, KARAKAIDOS P, et al.Activation of the DNA damage checkpoint and genomic instability inhuman precancerous lesions [J]. Nature,2005,434(7035):907-13.
[285] YAMAMOTO K, WANG Y, JIANG W, et al. Kinase-dead ATMprotein causes genomic instability and early embryonic lethality in mice[J]. The Journal of cell biology,2012,198(3):305-13.
[286] DANIEL J A, PELLEGRINI M, LEE B S, et al. Loss of ATMkinase activity leads to embryonic lethality in mice [J]. The Journal ofcell biology,2012,198(3):295-304.
[287] SHILOH Y, ZIV Y. The ATM protein: The importance of beingactive [J]. The Journal of cell biology,2012,198(3):273-5.
[288] HU H, DU L, NAGABAYASHI G, et al. ATM is down-regulatedby N-Myc-regulated microRNA-421[J]. Proceedings of the NationalAcademy of Sciences of the United States of America,2010,107(4):1506-11.
[289] YAN D, NG W L, ZHANG X, et al. Targeting DNA-PKcs andATM with miR-101sensitizes tumors to radiation [J]. PloS one,2010,5(7): e11397.
[290] NG W L, YAN D, ZHANG X, et al. Over-expression of miR-100is responsible for the low-expression of ATM in the human glioma cellline: M059J [J]. DNA repair,2010,9(11):1170-5.
[291] MORIN R D, O'CONNOR M D, GRIFFITH M, et al. Applicationof massively parallel sequencing to microRNA profiling and discovery inhuman embryonic stem cells [J]. Genome research,2008,18(4):610-21.
[292] MA F, LIU X, LI D, et al. MicroRNA-466l upregulates IL-10expression in TLR-triggered macrophages by antagonizing RNA-bindingprotein tristetraprolin-mediated IL-10mRNA degradation [J]. J Immunol,2010,184(11):6053-9.
[293] LI L C, OKINO S T, ZHAO H, et al. Small dsRNAs inducetranscriptional activation in human cells [J]. Proceedings of the NationalAcademy of Sciences of the United States of America,2006,103(46):17337-42.
[294] JANOWSKI B A, YOUNGER S T, HARDY D B, et al. Activatinggene expression in mammalian cells with promoter-targeted duplexRNAs [J]. Nature chemical biology,2007,3(3):166-73.
[295] PLACE R F, LI L C, POOKOT D, et al. MicroRNA-373inducesexpression of genes with complementary promoter sequences [J].Proceedings of the National Academy of Sciences of the United States ofAmerica,2008,105(5):1608-13.
[296] HUANG V, PLACE R F, PORTNOY V, et al. Upregulation ofCyclin B1by miRNA and its implications in cancer [J]. Nucleic acidsresearch,2012,40(4):1695-707.
[297] OROM U A, NIELSEN F C, LUND A H. MicroRNA-10a bindsthe5'UTR of ribosomal protein mRNAs and enhances their translation [J].Molecular cell,2008,30(4):460-71.
[298] JOPLING C L, YI M, LANCASTER A M, et al. Modulation ofhepatitis C virus RNA abundance by a liver-specific MicroRNA [J].Science,2005,309(5740):1577-81.
[299] ROBERTS A P, LEWIS A P, JOPLING C L. miR-122activateshepatitis C virus translation by a specialized mechanism requiringparticular RNA components [J]. Nucleic acids research,2011,39(17):7716-29.
[300] COLLER H A, SANG L, ROBERTS J M. A new description ofcellular quiescence [J]. PLoS biology,2006,4(3): e83.
[301] VASUDEVAN S. Posttranscriptional upregulation by microRNAs[J]. Wiley interdisciplinary reviews RNA,2012,3(3):311-30.
[302] VASUDEVAN S, STEITZ J A. AU-rich-element-mediatedupregulation of translation by FXR1and Argonaute2[J]. Cell,2007,128(6):1105-18.
[303] VASUDEVAN S, TONG Y, STEITZ J A. Switching fromrepression to activation: microRNAs can up-regulate translation [J].Science,2007,318(5858):1931-4.
[304] VASUDEVAN S, TONG Y, STEITZ J A. Cell-cycle control ofmicroRNA-mediated translation regulation [J]. Cell Cycle,2008,7(11):1545-9.
[305] MORTENSEN R D, SERRA M, STEITZ J A, et al.Posttranscriptional activation of gene expression in Xenopus laevisoocytes by microRNA-protein complexes (microRNPs)[J]. Proceedingsof the National Academy of Sciences of the United States of America,2011,108(20):8281-6.
[306] LEIVONEN S K, MAKELA R, OSTLING P, et al. Protein lysatemicroarray analysis to identify microRNAs regulating estrogen receptorsignaling in breast cancer cell lines [J]. Oncogene,2009,28(44):3926-36.
[307] SONG L, LIN C, WU Z, et al. miR-18a impairs DNA damageresponse through downregulation of ataxia telangiectasia mutated (ATM)kinase [J]. PloS one,2011,6(9): e25454.
[308] WICKRAMASINGHE N S, MANAVALAN T T, DOUGHERTYS M, et al. Estradiol downregulates miR-21expression and increasesmiR-21target gene expression in MCF-7breast cancer cells [J]. Nucleicacids research,2009,37(8):2584-95.
[309] DONG J, ZHAO Y P, ZHOU L, et al. Bcl-2upregulation inducedby miR-21via a direct interaction is associated with apoptosis andchemoresistance in MIA PaCa-2pancreatic cancer cells [J]. Archives ofmedical research,2011,42(1):8-14.
[310] LIN C C, LIU L Z, ADDISON J B, et al. A KLF4-miRNA-206autoregulatory feedback loop can promote or inhibit protein translationdepending upon cell context [J]. Molecular and cellular biology,2011,31(12):2513-27.
[311] NIEMOELLER O M, NIYAZI M, CORRADINI S, et al.MicroRNA expression profiles in human cancer cells after ionizingradiation [J]. Radiat Oncol,2011,6(29.
[312] GIRARDI C, DE PITTA C, CASARA S, et al. Analysis of miRNAand mRNA expression profiles highlights alterations in ionizing radiationresponse of human lymphocytes under modeled microgravity [J]. PloSone,2012,7(2): e31293.
[313] CHA H J, SHIN S, YOO H, et al. Identification of ionizingradiation-responsive microRNAs in the IM9human B lymphoblastic cellline [J]. International journal of oncology,2009,34(6):1661-8.
[314] SHIN S, CHA H J, LEE E M, et al. Alteration of miRNA profilesby ionizing radiation in A549human non-small cell lung cancer cells [J].International journal of oncology,2009,35(1):81-6.
[315] NIKIFOROVA M N, GANDHI M, KELLY L, et al. MicroRNAdysregulation in human thyroid cells following exposure to ionizingradiation [J]. Thyroid: official journal of the American ThyroidAssociation,2011,21(3):261-6.
[316] CHAUDHRY M A. Real-time PCR analysis of micro-RNAexpression in ionizing radiation-treated cells [J]. Cancer biotherapy&radiopharmaceuticals,2009,24(1):49-56.
[317] ZHU Y, YU X, FU H, et al. MicroRNA-21is involved in ionizingradiation-promoted liver carcinogenesis [J]. International journal ofclinical and experimental medicine,2010,3(3):211-22.
[318] LIANG Z, AHN J, GUO D, et al. MicroRNA-302ReplacementTherapy Sensitizes Breast Cancer Cells to Ionizing Radiation [J].Pharmaceutical research,2012,
[319] SIMONE N L, SOULE B P, LY D, et al. Ionizing radiation-induced oxidative stress alters miRNA expression [J]. PloS one,2009,4(7): e6377.
[320] CHAUDHRY M A, OMARUDDIN R A. Differential regulation ofmicroRNA expression in irradiated and bystander cells [J].Molekuliarnaia biologiia,2012,46(4):634-43.
[321] KULSHRESHTHA R, FERRACIN M, WOJCIK S E, et al. AmicroRNA signature of hypoxia [J]. Molecular and cellular biology,2007,27(5):1859-67.
[322] O'CONNELL R M, TAGANOV K D, BOLDIN M P, et al.MicroRNA-155is induced during the macrophage inflammatory response[J]. Proceedings of the National Academy of Sciences of the UnitedStates of America,2007,104(5):1604-9.
[323] LEE H J, PALKOVITS M, YOUNG W S,3RD. miR-7b, amicroRNA up-regulated in the hypothalamus after chronic hyperosmolarstimulation, inhibits Fos translation [J]. Proceedings of the NationalAcademy of Sciences of the United States of America,2006,103(42):15669-74.
[324] SALEH A D, SAVAGE J E, CAO L, et al. Cellular stress inducedalterations in microRNA let-7a and let-7b expression are dependent onp53[J]. PloS one,2011,6(10): e24429.
[325] TRABUCCHI M, BRIATA P, GARCIA-MAYORAL M, et al. TheRNA-binding protein KSRP promotes the biogenesis of a subset ofmicroRNAs [J]. Nature,2009,459(7249):1010-4.
[326] TRABUCCHI M, BRIATA P, FILIPOWICZ W, et al. KSRPpromotes the maturation of a group of miRNA precursors [J]. Advancesin experimental medicine and biology,2010,700(36-42.
[327] ZHANG X, WAN G, BERGER F G, et al. The ATM kinaseinduces microRNA biogenesis in the DNA damage response [J].Molecular cell,2011,41(4):371-83.
[328] LEUNG A K, SHARP P A. MicroRNA functions in stressresponses [J]. Molecular cell,2010,40(2):205-15.
[329] MARSIT C J, EDDY K, KELSEY K T. MicroRNA responses tocellular stress [J]. Cancer research,2006,66(22):10843-8.
[330] HUO J, QIN F, CAI X, et al. Chinese medicine formula "WeikangKeli" induces autophagic cell death on human gastric cancer cell lineSGC-7901[J]. Phytomedicine: international journal of phytotherapy andphytopharmacology,2012,
[331] SHIMIZU S, KANASEKI T, MIZUSHIMA N, et al. Role of Bcl-2family proteins in a non-apoptotic programmed cell death dependent onautophagy genes [J]. Nature cell biology,2004,6(12):1221-8.
[332] ESPERT L, DENIZOT M, GRIMALDI M, et al. Autophagy isinvolved in T cell death after binding of HIV-1envelope proteins toCXCR4[J]. The Journal of clinical investigation,2006,116(8):2161-72.
[333] SALAZAR M, CARRACEDO A, SALANUEVA I J, et al.Cannabinoid action induces autophagy-mediated cell death throughstimulation of ER stress in human glioma cells [J]. The Journal of clinicalinvestigation,2009,119(5):1359-72.
[334] QU X, ZOU Z, SUN Q, et al. Autophagy gene-dependent clearanceof apoptotic cells during embryonic development [J]. Cell,2007,128(5):931-46.
[335] LEMASTERS J J. Selective mitochondrial autophagy, ormitophagy, as a targeted defense against oxidative stress, mitochondrialdysfunction, and aging [J]. Rejuvenation research,2005,8(1):3-5.
[336] DING W X, NI H M, GAO W, et al. Linking of autophagy toubiquitin-proteasome system is important for the regulation ofendoplasmic reticulum stress and cell viability [J]. The American journalof pathology,2007,171(2):513-24.
[337] OGATA M, HINO S, SAITO A, et al. Autophagy is activated forcell survival after endoplasmic reticulum stress [J]. Molecular andcellular biology,2006,26(24):9220-31.
[338] BERNALES S, MCDONALD K L, WALTER P. Autophagycounterbalances endoplasmic reticulum expansion during the unfoldedprotein response [J]. PLoS biology,2006,4(12): e423.
[339] KOMATSU M, WAGURI S, UENO T, et al. Impairment ofstarvation-induced and constitutive autophagy in Atg7-deficient mice [J].The Journal of cell biology,2005,169(3):425-34.
[340] KUMA A, HATANO M, MATSUI M, et al. The role of autophagyduring the early neonatal starvation period [J]. Nature,2004,432(7020):1032-6.
[341] BOYA P, GONZALEZ-POLO R A, CASARES N, et al. Inhibitionof macroautophagy triggers apoptosis [J]. Molecular and cellular biology,2005,25(3):1025-40.
[342] GONZALEZ-POLO R A, BOYA P, PAULEAU A L, et al. Theapoptosis/autophagy paradox: autophagic vacuolization before apoptoticdeath [J]. Journal of cell science,2005,118(Pt14):3091-102.
[343] GUMP J M, THORBURN A. Autophagy and apoptosis: what isthe connection?[J]. Trends in cell biology,2011,21(7):387-92.
[344] DEGENHARDT K, MATHEW R, BEAUDOIN B, et al.Autophagy promotes tumor cell survival and restricts necrosis,inflammation, and tumorigenesis [J]. Cancer cell,2006,10(1):51-64.
[345] SAMARA C, SYNTICHAKI P, TAVERNARAKIS N. Autophagyis required for necrotic cell death in Caenorhabditis elegans [J]. Celldeath and differentiation,2008,15(1):105-12.
[346] KROEMER G, MARINO G, LEVINE B. Autophagy and theintegrated stress response [J]. Molecular cell,2010,40(2):280-93.
[347] HIPPERT M M, O'TOOLE P S, THORBURN A. Autophagy incancer: good, bad, or both?[J]. Cancer research,2006,66(19):9349-51.
[348] EISENBERG-LERNER A, KIMCHI A. The paradox of autophagyand its implication in cancer etiology and therapy [J]. Apoptosis: aninternational journal on programmed cell death,2009,14(4):376-91.
[349] GEWIRTZ D A, HILLIKER M L, WILSON E N. Promotion ofautophagy as a mechanism for radiation sensitization of breast tumor cells[J]. Radiotherapy and oncology: journal of the European Society forTherapeutic Radiology and Oncology,2009,92(3):323-8.
[350] ZOIS C E, KOUKOURAKIS M I. Radiation-induced autophagy innormal and cancer cells: towards novel cytoprotection and radio-sensitization policies?[J]. Autophagy,2009,5(4):442-50.
[351] CAO C, SUBHAWONG T, ALBERT J M, et al. Inhibition ofmammalian target of rapamycin or apoptotic pathway induces autophagyand radiosensitizes PTEN null prostate cancer cells [J]. Cancer research,2006,66(20):10040-7.
[352] MORETTI L, ATTIA A, KIM K W, et al. Crosstalk betweenBak/Bax and mTOR signaling regulates radiation-induced autophagy [J].Autophagy,2007,3(2):142-4.
[353] YUK J M, SHIN D M, SONG K S, et al. Bacillus calmette-guerincell wall cytoskeleton enhances colon cancer radiosensitivity throughautophagy [J]. Autophagy,2010,6(1):46-60.
[354] PAN J, CHEN B, SU C H, et al. Autophagy induced byfarnesyltransferase inhibitors in cancer cells [J]. Cancer biology&therapy,2008,7(10):1679-84.
[355] SMITH E L, SCHUCHMAN E H. Acid sphingomyelinaseoverexpression enhances the antineoplastic effects of irradiation in vitroand in vivo [J]. Molecular therapy: the journal of the American Societyof Gene Therapy,2008,16(9):1565-71.
[356] DEMASTERS G, DI X, NEWSHAM I, et al. Potentiation ofradiation sensitivity in breast tumor cells by the vitamin D3analogue, EB1089, through promotion of autophagy and interference with proliferativerecovery [J]. Molecular cancer therapeutics,2006,5(11):2786-97.
[357] TSUBOI Y, KURIMOTO M, NAGAI S, et al. Induction ofautophagic cell death and radiosensitization by the pharmacologicalinhibition of nuclear factor-kappa B activation in human glioma cell lines[J]. Journal of neurosurgery,2009,110(3):594-604.
[358] CHAACHOUAY H, OHNESEIT P, TOULANY M, et al.Autophagy contributes to resistance of tumor cells to ionizing radiation[J]. Radiotherapy and oncology: journal of the European Society forTherapeutic Radiology and Oncology,2011,99(3):287-92.
[359] LOMONACO S L, FINNISS S, XIANG C, et al. The induction ofautophagy by gamma-radiation contributes to the radioresistance ofglioma stem cells [J]. International journal of cancer Journal internationaldu cancer,2009,125(3):717-22.
[360] APEL A, HERR I, SCHWARZ H, et al. Blocked autophagysensitizes resistant carcinoma cells to radiation therapy [J]. Cancerresearch,2008,68(5):1485-94.
[361] NOTTE A, LECLERE L, MICHIELS C. Autophagy as a mediatorof chemotherapy-induced cell death in cancer [J]. Biochemicalpharmacology,2011,82(5):427-34.
[362] XIONG H Y, GUO X L, BU X X, et al. Autophagic cell deathinduced by5-FU in Bax or PUMA deficient human colon cancer cell [J].Cancer letters,2010,288(1):68-74.
[363] LI J, HOU N, FARIED A, et al. Inhibition of autophagy augments5-fluorouracil chemotherapy in human colon cancer in vitro and in vivomodel [J]. Eur J Cancer,2010,46(10):1900-9.
[364] MIKI H, UEHARA N, KIMURA A, et al. Resveratrol inducesapoptosis via ROS-triggered autophagy in human colon cancer cells [J].International journal of oncology,2012,40(4):1020-8.
[365] LEE Y J, KIM N Y, SUH Y A, et al. Involvement of ROS inCurcumin-induced Autophagic Cell Death [J]. The Korean journal ofphysiology&pharmacology: official journal of the Korean PhysiologicalSociety and the Korean Society of Pharmacology,2011,15(1):1-7.
[366] JOHN S, MLS J, CERVINKA M, et al. The Role of AutophagicCell Death and Apoptosis in Irinotecan-Treated P53Null Colon CancerCells [J]. Anti-cancer agents in medicinal chemistry,2012,
[367] MARTIN A P, MITCHELL C, RAHMANI M, et al. Inhibition ofMCL-1enhances lapatinib toxicity and overcomes lapatinib resistance viaBAK-dependent autophagy [J]. Cancer biology&therapy,2009,8(21):2084-96.
[368] VERDOODT B, VOGT M, SCHMITZ I, et al. Salinomycininduces autophagy in colon and breast cancer cells with concomitantgeneration of reactive oxygen species [J]. PloS one,2012,7(9): e44132.
[369] XIE C M, CHAN W Y, YU S, et al. Bufalin induces autophagy-mediated cell death in human colon cancer cells through reactive oxygenspecies generation and JNK activation [J]. Free radical biology&medicine,2011,51(7):1365-75.
[370] SHINGU T, FUJIWARA K, BOGLER O, et al. Stage-specificeffect of inhibition of autophagy on chemotherapy-induced cytotoxicity[J]. Autophagy,2009,5(4):537-9.
[371] ZHOU S, ZHAO L, KUANG M, et al. Autophagy in tumorigenesisand cancer therapy: Dr. Jekyll or Mr. Hyde?[J]. Cancer letters,2012,323(2):115-27.
[372] HOYER-HANSEN M, JAATTELA M. Autophagy: an emergingtarget for cancer therapy [J]. Autophagy,2008,4(5):574-80.
[373] ZHU H, WU H, LIU X, et al. Regulation of autophagy by a beclin1-targeted microRNA, miR-30a, in cancer cells [J]. Autophagy,2009,5(6):816-23.
[374] ZOU Z, WU L, DING H, et al. MicroRNA-30a sensitizes tumorcells to cis-platinum via suppressing beclin1-mediated autophagy [J].The Journal of biological chemistry,2012,287(6):4148-56.
[375] KORKMAZ G, LE SAGE C, TEKIRDAG K A, et al. miR-376bcontrols starvation and mTOR inhibition-related autophagy by targetingATG4C and BECN1[J]. Autophagy,2012,8(2):165-76.
[376] YU Y, CAO L, YANG L, et al. microRNA30A promotesautophagy in response to cancer therapy [J]. Autophagy,2012,8(5):853-5.
[377] KOVALEVA V, MORA R, PARK Y J, et al. miRNA-130a targetsATG2B and DICER1to inhibit autophagy and trigger killing of chroniclymphocytic leukemia cells [J]. Cancer research,2012,72(7):1763-72.
[378] XIAO J, ZHU X, HE B, et al. MiR-204regulates cardiomyocyteautophagy induced by ischemia-reperfusion through LC3-II [J]. Journalof biomedical science,2011,18(35.
[379] UCAR A, GUPTA S K, FIEDLER J, et al. The miRNA-212/132family regulates both cardiac hypertrophy and cardiomyocyte autophagy[J]. Nature communications,2012,3(1078.
[380] FRANKEL L B, WEN J, LEES M, et al. microRNA-101is apotent inhibitor of autophagy [J]. The EMBO journal,2011,30(22):4628-41.
[381] CHANG Y, YAN W, HE X, et al. miR-375inhibits autophagy andreduces viability of hepatocellular carcinoma cells under hypoxicconditions [J]. Gastroenterology,2012,143(1):177-87e8.
[382] CHEN Y, LIERSCH R, DETMAR M. The miR-290-295clustersuppresses autophagic cell death of melanoma cells [J]. Scientific reports,2012,2(808.
[383] TSUCHIDA A, OHNO S, WU W, et al. miR-92is a key oncogeniccomponent of the miR-17-92cluster in colon cancer [J]. Cancer science,2011,102(12):2264-71.
[384] CORRADETTI M N, GUAN K L. Upstream of the mammaliantarget of rapamycin: do all roads pass through mTOR?[J]. Oncogene,2006,25(48):6347-60.
[385] MATHEW R, KARP C M, BEAUDOIN B, et al. Autophagysuppresses tumorigenesis through elimination of p62[J]. Cell,2009,137(6):1062-75.
[386] MOSCAT J, DIAZ-MECO M T. p62at the crossroads ofautophagy, apoptosis, and cancer [J]. Cell,2009,137(6):1001-4.
[387] PUISSANT A, FENOUILLE N, AUBERGER P. When autophagymeets cancer through p62/SQSTM1[J]. American journal of cancerresearch,2012,2(4):397-413.
[388] WANG Z, CAO L, KANG R, et al. Autophagy regulates myeloidcell differentiation by p62/SQSTM1-mediated degradation of PML-RARalpha oncoprotein [J]. Autophagy,2011,7(4):401-11.
[389] YANG Z J, CHEE C E, HUANG S, et al. Autophagy modulationfor cancer therapy [J]. Cancer biology&therapy,2011,11(2):169-76.
[390] BOHENSKY J, SHAPIRO I M, LESHINSKY S, et al. HIF-1regulation of chondrocyte apoptosis: induction of the autophagic pathway[J]. Autophagy,2007,3(3):207-14.
[391] ZHANG H, BOSCH-MARCE M, SHIMODA L A, et al.Mitochondrial autophagy is an HIF-1-dependent adaptive metabolicresponse to hypoxia [J]. The Journal of biological chemistry,2008,283(16):10892-903.
[392] BELIBI F, ZAFAR I, RAVICHANDRAN K, et al. Hypoxia-inducible factor-1alpha (HIF-1alpha) and autophagy in polycystic kidneydisease (PKD)[J]. American journal of physiology Renal physiology,2011,300(5): F1235-43.
[393] ZHAO Y, CHEN G, ZHANG W, et al. Autophagy regulateshypoxia-induced osteoclastogenesis through the HIF-1alpha/BNIP3signaling pathway [J]. Journal of cellular physiology,2012,227(2):639-48.
[394] BOSSEL BEN-MOSHE N, AVRAHAM R, KEDMI M, et al.Context-specific microRNA analysis: identification of functionalmicroRNAs and their mRNA targets [J]. Nucleic acids research,2012,40(21):10614-27.
[395] WEIDHAAS J B, BABAR I, NALLUR S M, et al. MicroRNAs aspotential agents to alter resistance to cytotoxic anticancer therapy [J].Cancer research,2007,67(23):11111-6.
[396] JOSSON S, SUNG S Y, LAO K, et al. Radiation modulation ofmicroRNA in prostate cancer cell lines [J]. The Prostate,2008,68(15):1599-606.
[397] GLIMELIUS B. Radiotherapy in rectal cancer [J]. British medicalbulletin,2002,64(141-57.
[398] GRABSCH H, DATTANI M, BARKER L, et al. Expression ofDNA double-strand break repair proteins ATM and BRCA1predictssurvival in colorectal cancer [J]. Clinical cancer research: an officialjournal of the American Association for Cancer Research,2006,12(5):1494-500.
[399] BEGGS A D, DOMINGO E, MCGREGOR M, et al. Loss ofexpression of the double strand break repair protein ATM is associatedwith worse prognosis in colorectal cancer and loss of Ku70expression isassociated with CIN [J]. Oncotarget,2012,3(11):1348-55.
[400] WU Y, LIU G L, LIU S H, et al. MicroRNA-148b enhances theradiosensitivity of non-Hodgkin's Lymphoma cells by promotingradiation-induced apoptosis [J]. Journal of radiation research,2012,53(4):516-25.
[401] HUANG S, LI X Q, CHEN X, et al. Inhibition of microRNA-21increases radiosensitivity of esophageal cancer cells through phosphataseand tensin homolog deleted on chromosome10activation [J]. Diseases ofthe esophagus: official journal of the International Society for Diseasesof the Esophagus/ISDE,2012,
[402] ZHANG S, WAN Y, PAN T, et al. MicroRNA-21inhibitorsensitizes human glioblastoma U251stem cells to chemotherapeutic drugtemozolomide [J]. Journal of molecular neuroscience: MN,2012,47(2):346-56.
[403] LEE K M, CHOI E J, KIM I A. microRNA-7increasesradiosensitivity of human cancer cells with activated EGFR-associatedsignaling [J]. Radiotherapy and oncology: journal of the EuropeanSociety for Therapeutic Radiology and Oncology,2011,101(1):171-6.
[404] NASSER M W, DATTA J, NUOVO G, et al. Down-regulation ofmicro-RNA-1(miR-1) in lung cancer. Suppression of tumorigenicproperty of lung cancer cells and their sensitization to doxorubicin-induced apoptosis by miR-1[J]. The Journal of biological chemistry,2008,283(48):33394-405.
[405] XIA L, ZHANG D, DU R, et al. miR-15b and miR-16modulatemultidrug resistance by targeting BCL2in human gastric cancer cells [J].International journal of cancer Journal international du cancer,2008,123(2):372-9.
[406] HUMMEL R, HUSSEY D J, HAIER J. MicroRNAs: predictorsand modifiers of chemo-and radiotherapy in different tumour types [J].Eur J Cancer,2010,46(2):298-311.
[407] HAYASHITA Y, OSADA H, TATEMATSU Y, et al. Apolycistronic microRNA cluster, miR-17-92, is overexpressed in humanlung cancers and enhances cell proliferation [J]. Cancer research,2005,65(21):9628-32.
[408] OTA A, TAGAWA H, KARNAN S, et al. Identification andcharacterization of a novel gene, C13orf25, as a target for13q31-q32amplification in malignant lymphoma [J]. Cancer research,2004,64(9):3087-95.
[409] HERMSEN M, POSTMA C, BAAK J, et al. Colorectal adenoma tocarcinoma progression follows multiple pathways of chromosomalinstability [J]. Gastroenterology,2002,123(4):1109-19.
[410] TANZER A, STADLER P F. Molecular evolution of a microRNAcluster [J]. Journal of molecular biology,2004,339(2):327-35.
[411] HE L, THOMSON J M, HEMANN M T, et al. A microRNApolycistron as a potential human oncogene [J]. Nature,2005,435(7043):828-33.
[412] XIANG J, WU J. Feud or Friend? The Role of the miR-17-92Cluster in Tumorigenesis [J]. Current genomics,2010,11(2):129-35.
[413] YU G, TANG J Q, TIAN M L, et al. Prognostic values of the miR-17-92cluster and its paralogs in colon cancer [J]. Journal of surgicaloncology,2012,106(3):232-7.
[414] STEMBALSKA A, BLIN N, RAMSEY D, et al. Three distinctregions of deletion on13q in squamous cell carcinoma of the larynx [J].Oncology reports,2006,16(2):417-21.
[415] ZHANG X L, FU W L, ZHAO H X, et al. Molecular studies of lossof heterozygosity in Chinese sporadic retinoblastoma patients [J]. Clinicachimica acta; international journal of clinical chemistry,2005,358(1-2):75-80.
[416] LIN Y W, SHEU J C, LIU L Y, et al. Loss of heterozygosity atchromosome13q in hepatocellular carcinoma: identification of threeindependent regions [J]. Eur J Cancer,1999,35(12):1730-4.
[417] EIRIKSDOTTIR G, JOHANNESDOTTIR G, INGVARSSON S,et al. Mapping loss of heterozygosity at chromosome13q: loss at13q12-q13is associated with breast tumour progression and poor prognosis [J].Eur J Cancer,1998,34(13):2076-81.
[418] LO K W, TEO P M, HUI A B, et al. High resolution allelotype ofmicrodissected primary nasopharyngeal carcinoma [J]. Cancer research,2000,60(13):3348-53.
[419] ZHANG L, HUANG J, YANG N, et al. microRNAs exhibit highfrequency genomic alterations in human cancer [J]. Proceedings of theNational Academy of Sciences of the United States of America,2006,103(24):9136-41.
[420] OLIVE V, JIANG I, HE L. mir-17-92, a cluster of miRNAs in themidst of the cancer network [J]. The international journal of biochemistry&cell biology,2010,42(8):1348-54.
[421] LI T, CHEN J X, FU X P, et al. microRNA expression profiling ofnasopharyngeal carcinoma [J]. Oncology reports,2011,25(5):1353-63.
[422] YAO Y, SUO A L, LI Z F, et al. MicroRNA profiling of humangastric cancer [J]. Molecular medicine reports,2009,2(6):963-70.
[423] ALENCAR A J, MALUMBRES R, KOZLOSKI G A, et al.MicroRNAs are independent predictors of outcome in diffuse large B-celllymphoma patients treated with R-CHOP [J]. Clinical cancer research: anofficial journal of the American Association for Cancer Research,2011,17(12):4125-35.
[424] AYALA DE LA PENA F, KANASAKI K, KANASAKI M, et al.Loss of p53and acquisition of angiogenic microRNA profile areinsufficient to facilitate progression of bladder urothelial carcinoma insitu to invasive carcinoma [J]. The Journal of biological chemistry,2011,286(23):20778-87.
[425] MOTOYAMA K, INOUE H, TAKATSUNO Y, et al. Over-andunder-expressed microRNAs in human colorectal cancer [J]. Internationaljournal of oncology,2009,34(4):1069-75.
[426] MORIMURA R, KOMATSU S, ICHIKAWA D, et al. Noveldiagnostic value of circulating miR-18a in plasma of patients withpancreatic cancer [J]. British journal of cancer,2011,105(11):1733-40.
[427] LOVEN J, ZININ N, WAHLSTROM T, et al. MYCN-regulatedmicroRNAs repress estrogen receptor-alpha (ESR1) expression andneuronal differentiation in human neuroblastoma [J]. Proceedings of theNational Academy of Sciences of the United States of America,2010,107(4):1553-8.
[428] LIU W H, YEH S H, LU C C, et al. MicroRNA-18a preventsestrogen receptor-alpha expression, promoting proliferation ofhepatocellular carcinoma cells [J]. Gastroenterology,2009,136(2):683-93.
[429] TAO J, WU D, LI P, et al. microRNA-18a, a member of theoncogenic miR-17-92cluster, targets Dicer and suppresses cellproliferation in bladder cancer T24cells [J]. Molecular medicine reports,2012,5(1):167-72.
[430] LUO Z, DAI Y, ZHANG L, et al. miR-18a promotes malignantprogression by impairing microRNA biogenesis in nasopharyngealcarcinoma [J]. Carcinogenesis,2012,
[431] FOX J L, DEWS M, MINN A J, et al. Targeting of TGFbetasignature and its essential component CTGF by miR-18correlates withimproved survival in glioblastoma [J]. RNA,2012,
[432] YAMADA N A, CASTRO A, FARBER R A. Variation in theextent of microsatellite instability in human cell lines with defects indifferent mismatch repair genes [J]. Mutagenesis,2003,18(3):277-82.
[433] YEUNG T M, GANDHI S C, WILDING J L, et al. Cancer stemcells from colorectal cancer-derived cell lines [J]. Proceedings of theNational Academy of Sciences of the United States of America,2010,107(8):3722-7.
[434] HUMPHREYS K J, COBIAC L, LE LEU R K, et al. Histonedeacetylase inhibition in colorectal cancer cells reveals competing rolesfor members of the oncogenic miR-17-92cluster [J]. Molecularcarcinogenesis,2012,
[435] LI Y, BAVARVA J H, WANG Z, et al. HEF1, a novel target ofWnt signaling, promotes colonic cell migration and cancer progression [J].Oncogene,2011,30(23):2633-43.
[436] XIA D, HOLLA V R, WANG D, et al. HEF1is a crucial mediatorof the proliferative effects of prostaglandin E(2) on colon cancer cells [J].Cancer research,2010,70(2):824-31.
[437] MALUMBRES M, HARLOW E, HUNT T, et al. Cyclin-dependent kinases: a family portrait [J]. Nature cell biology,2009,11(11):1275-6.
[438] FIRESTEIN R, BASS A J, KIM S Y, et al. CDK8is a colorectalcancer oncogene that regulates beta-catenin activity [J]. Nature,2008,455(7212):547-51.
[439] SHEN K C, HENG H, WANG Y, et al. ATM and p21cooperate tosuppress aneuploidy and subsequent tumor development [J]. Cancerresearch,2005,65(19):8747-53.
[440]JIEMJIT A, FANDY T E, CARRAWAY H, et al. p21(WAF1/CIP1)induction by5-azacytosine nucleosides requires DNA damage [J].Oncogene,2008,27(25):3615-23.
[441] TSANG W P, KWOK T T. The miR-18a*microRNA functions asa potential tumor suppressor by targeting on K-Ras [J]. Carcinogenesis,2009,30(6):953-9.
[442] ZHANG J, XIAO Z, LAI D, et al. miR-21, miR-17and miR-19ainduced by phosphatase of regenerating liver-3promote the proliferationand metastasis of colon cancer [J]. British journal of cancer,2012,107(2):352-9.
[443] OLIVE V, BENNETT M J, WALKER J C, et al. miR-19is a keyoncogenic component of mir-17-92[J]. Genes&development,2009,23(24):2839-49.
[444] CASTELLANO L, GIAMAS G, JACOB J, et al. The estrogenreceptor-alpha-induced microRNA signature regulates itself and itstranscriptional response [J]. Proceedings of the National Academy ofSciences of the United States of America,2009,106(37):15732-7.
[445] HAGGAR F A, BOUSHEY R P. Colorectal cancer epidemiology:incidence, mortality, survival, and risk factors [J]. Clinics in colon andrectal surgery,2009,22(4):191-7.
[446] RAJAGOPALAN H, NOWAK M A, VOGELSTEIN B, et al. Thesignificance of unstable chromosomes in colorectal cancer [J]. Naturereviews Cancer,2003,3(9):695-701.
[447] BARTKOVA J, REZAEI N, LIONTOS M, et al. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNAdamage checkpoints [J]. Nature,2006,444(7119):633-7.
[448] GORGOULIS V G, HALAZONETIS T D. Oncogene-inducedsenescence: the bright and dark side of the response [J]. Current opinionin cell biology,2010,22(6):816-27.
[449] KWONG L N, WEISS K R, HAIGIS K M, et al. Atm is a negativeregulator of intestinal neoplasia [J]. Oncogene,2008,27(7):1013-8.
[450] GAO C, CAO W, BAO L, et al. Autophagy negatively regulatesWnt signalling by promoting Dishevelled degradation [J]. Nature cellbiology,2010,12(8):781-90.
[451] POLAKIS P. Wnt signaling in cancer [J]. Cold Spring Harborperspectives in biology,2012,4(5):
[452] BAKIRTZI K, HATZIAPOSTOLOU M, KARAGIANNIDES I, etal. Neurotensin signaling activates microRNAs-21and-155and Akt,promotes tumor growth in mice, and is increased in human colon tumors[J]. Gastroenterology,2011,141(5):1749-61e1.
[453] COTTONHAM C L, KANEKO S, XU L. miR-21and miR-31converge on TIAM1to regulate migration and invasion of coloncarcinoma cells [J]. The Journal of biological chemistry,2010,285(46):35293-302.
[454] FALTEJSKOVA P, BESSE A, SEVCIKOVA S, et al. Clinicalcorrelations of miR-21expression in colorectal cancer patients and effectsof its inhibition on DLD1colon cancer cells [J]. International journal ofcolorectal disease,2012,27(11):1401-8.
[455] WU J, WU G, LV L, et al. MicroRNA-34a inhibits migration andinvasion of colon cancer cells via targeting to Fra-1[J]. Carcinogenesis,2012,33(3):519-28.
[456] CAMPANER S, AMATI B. Two sides of the Myc-induced DNAdamage response: from tumor suppression to tumor maintenance [J]. Celldivision,2012,7(1):6.
[457] PUSAPATI R V, ROUNBEHLER R J, HONG S, et al. ATMpromotes apoptosis and suppresses tumorigenesis in response to Myc [J].Proceedings of the National Academy of Sciences of the United States ofAmerica,2006,103(5):1446-51.
[458] VAN HAAFTEN G, AGAMI R. Tumorigenicity of the miR-17-92cluster distilled [J]. Genes&development,2010,24(1):1-4.