NGX6基因对结肠癌血管形成及凋亡影响的研究
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摘要
NGX6基因是中南大学肿瘤研究所分子遗传室在对鼻咽癌研究中筛选克隆出的一个新基因(Genbank号AF188239)。生物信息学分析显示：NGX6基因cDNA全长2134bp,编码蛋白含338个氨基酸,预测分子量37kDa,含有2个跨膜结构域,胞外区含有1个表皮生长因子(EGF)样结构域和3个糖基化位点,胞内区较短,含有一个酪氨酸激酶磷酸化位点。
前期对NGX6基因的研究中发现：NGX6在鼻咽癌活检组织、鼻咽癌上皮细胞株中表达下调甚至缺失,在正常鼻咽组织中存在明确的表达；NGX6基因在结直肠癌中亦存在不同程度的表达下调,且伴有淋巴结转移的结直肠癌样本当中NGX6表达下调的比例(15/16)远高于无淋巴结转移的结直肠癌样本(25/34)；利用高通量的组织芯片进行的原位杂交实验发现,NGX6基因的表达在有转移的肿瘤组织下调更明显,且与临床分期相关；将NGX6基因分别转染鼻咽癌和结肠癌细胞之后可以使鼻咽癌细胞和结肠癌细胞的恶性表型得到部分逆转(通过细胞周期、细胞生长曲线、软琼脂集落形成、裸鼠接种等实验获得的数据)；并使鼻咽癌和结肠癌细胞的基因/蛋白质表达谱发生某些改变及表皮生长因子受体的磷酸化水平下降；利用绿色荧光蛋白发现NGX6的亚细胞定位主要是细胞膜。
NGX6基因作为具有一个酪氨酸激酶磷酸化位点的膜蛋白,提示了NGX6基因参与细胞内信号传导的一种可能。NGX6基因胞外区含有1个表皮生长因子(EGF)样结构域,EGF样结构域主要和受体一配体间交互作用有关,提示NGX6基因在细胞信号传导中应与有生长因子样结构的膜蛋白有着协同或拮抗作用。同时前期研究证明NGX6基因可以使表皮生长因子受体(EGFR)的磷酸化水平下降,提示NGX6基因可能调控EGFR通路,影响NF-κB的活化,影响肿瘤的发生、发展。
在前期研究工作的基础上,结合对NGX6基因生物信息学特征分析的结果,本研究为进一步对NGX6基因功能的探讨做了如下实验：
1.利用已构建好的pcDNA3.1(+)／NGX6／HT-29结肠癌细胞,通过鸡胚绒毛尿囊膜血管(CAM)形成实验,将结肠癌细胞接种到鸡胚绒毛尿囊膜,发现NGX6基因抑制了鸡胚绒毛尿囊膜血管的形成；将结肠癌细胞接种到裸鼠腋前皮下,发现NGX6基因抑制了结肠癌种植瘤的生长,将种植瘤切片分析证实NGX6基因抑制了结肠癌种植瘤内血管的形成,抑制了种植瘤血管内癌栓的形成,并且抑制了结肠癌的转移；RT-PCR实验表明NGX6基因下调了结肠癌细胞及结肠癌种植瘤内VEGF的表达。这些实验结果表明NGX6基因抑制了结肠癌的血管形成,进而影响了肿瘤的发展及转移。
2.通过PI／Annexin-V双染流式细胞仪检测发现,对于在体外培养的结肠癌细胞,转染了NGX6基因的与未转染的比较,凋亡并无差别,基本上全都是正常的活细胞；通过EMSA分析结肠癌细胞核蛋白,转染了NGX6基因的结肠癌HT-29细胞NF-κB激活明显受到抑制；将结肠癌细胞接种到裸鼠腋前皮下,将种植瘤通过PI／Annexin-V双染流式细胞仪检测发现转染了NGX6基因的与未转染的比较,凋亡率明显增高；与化疗药物5-Fu联用后,NGX6基因明显诱导了结肠癌细胞的凋亡。这些实验结果说明NGX6基因通过抑制结肠癌细胞NF-κB的激活,促进了结肠癌细胞的凋亡。
NGX6基因抑制VEGF的表达以及NF-κB的激活间接说明NGX6基因在细胞信号传导中与EGFR信号通路起拮抗作用。本实验说明NGX6基因能抑制肿瘤血管形成以及诱导肿瘤细胞凋亡,此结果为证实NGX6基因是一个抑瘤基因提供一个强有力的证明。结肠癌的侵袭转移是其致命的威胁,本研究中发现NGX6基因抑制了结肠癌的转移,此结果表明NGX6基因对结肠癌患者预后有着积极的影响作用。但是要确定NGX6基因具体的生物学功能以及更为详尽的机制有待以后进一步的研究。
The novel gene NGX6 is isolated by tumor laboratory of Central South University on studying nasopharyngeal carcinoma. NGX6 gene is located on the chromosome 9p21-22. The full-length of NGX6 cDNA is 2134 bp, encoding a polypeptide of 338 amino acids with a predicated molecular weight of 37 kDa. NGX6 protein includes two transmemberane regions. There are an EGF-like domain signature and three potential N-glycosylation sites in the extracellular domain of it. The short cytoplasm contains a tyrosine residue that is a potential phsophorylation site by tyrosine kinase.
Previous study on NGX6 showed:in normal nasopharyngeal epithelial tissues, NGX6 was expressed in high level, while in very low level or undetectable in nasopharyngeal carcinoma biopsies and cell line. NGX6 also be found down-regulated in colorectal carcinomas, and expression of NGX6 was down-regulated in the tumors with metastasis and related to the clinic stages by using the in suit hybridization and tissue array techniques. Transfection of NGX6 into nasopharyngeal and colorectal carcinomas cells can induce the reversion of some malignant phenotypes (data obtained from cell cycle, cell growth rate curve, soft agar colony formation, nude mice injection analysis, et al), the changes of gene/protein expression profiles and the down-regulation of expression of phosphor-EGFR. NGX6 protein mostly is located on cell membrane by using a GFP-NGX6 fusion protein.
NGX6 contains a tyrosine residue that indicate NGX6 maybe influence the cellular signal transduction. And NGX6 contains an EGF-like domain that indicate NGX6 maybe antagonist or work in coordination with proteins with the same construction.
Based on these studies, in an attempt to identify the function of NGX6, we designed the experiments:1. The NGX6-transfected HT-29 cell line was used as the test, empty-vector-transfected HT-29 cell line and untransfected HT-29 cell line were used as the control. The effect of NGX6 in angiogenesis was detected by The CAM experiment and animal model. The CAM experiment and animal model showed the NGX6 gene can inhibite angiogenesis. And the express of VEGF was detected by RT-PCR, that showed the expression of VEGF was down-regulated by NGX6 gene. And there are metastasis in lung of mice were confirmed by hematoxylin-eosin staining Both in PcDNA3.1(+)/HT-29 group and HT-29 group, but there is no found in pcDNA3.1(+)/NGX6/HT-29 group. The NGX6 gene inhibited the metastasis of colon cancer.
2. The effect of NGX6 on Apoptosis was detected by FCM cells were double-stained by PI/Annexin-V. There is no difference of Apoptosis between NGX6 transfected colon carcinoma cells and NGX6 untransfected colon carcinoma cell when cells are cultivated in vitro. But apoptosis level of NGX6 transfected colon carcinoma cells of xenograft tumor in nude mice is higher than that of NGX6 untransfected colon carcinoma cells. The NGX6-transfected HT-29 cell line with 5-Fu was used as the test, HT-29 cell line with 5-Fu and PDTC was used as the control. NGX6 gene obviously enhanced the effects of anti-proliferation and inducing apoptosis of 5-Fu. The express of NF-kB was detected by EMSA. And the express of NF-κB is inhibited in NGX6 transfected colon carcinoma cell groups. These experiments showed NGX6 gene can induce apoptosis of colon cancer and inhibit the expression of NF-κB.
These experiments showed NGX6 gene can inhibite the expression of VEGF and NF-κB. And They also showed that NGX6 gene enhanced the effects of inducing apoptosis and anti-proliferation of colon carcinoma. But it needs more experiments to collect more evidences to understand the exact biological function of NGX6 and its role in the carcinoma.
前期对NGX6基因的研究中发现：NGX6在鼻咽癌活检组织、鼻咽癌上皮细胞株中表达下调甚至缺失,在正常鼻咽组织中存在明确的表达；NGX6基因在结直肠癌中亦存在不同程度的表达下调,且伴有淋巴结转移的结直肠癌样本当中NGX6表达下调的比例(15/16)远高于无淋巴结转移的结直肠癌样本(25/34)；利用高通量的组织芯片进行的原位杂交实验发现,NGX6基因的表达在有转移的肿瘤组织下调更明显,且与临床分期相关；将NGX6基因分别转染鼻咽癌和结肠癌细胞之后可以使鼻咽癌细胞和结肠癌细胞的恶性表型得到部分逆转(通过细胞周期、细胞生长曲线、软琼脂集落形成、裸鼠接种等实验获得的数据)；并使鼻咽癌和结肠癌细胞的基因/蛋白质表达谱发生某些改变及表皮生长因子受体的磷酸化水平下降；利用绿色荧光蛋白发现NGX6的亚细胞定位主要是细胞膜。
NGX6基因作为具有一个酪氨酸激酶磷酸化位点的膜蛋白,提示了NGX6基因参与细胞内信号传导的一种可能。NGX6基因胞外区含有1个表皮生长因子(EGF)样结构域,EGF样结构域主要和受体一配体间交互作用有关,提示NGX6基因在细胞信号传导中应与有生长因子样结构的膜蛋白有着协同或拮抗作用。同时前期研究证明NGX6基因可以使表皮生长因子受体(EGFR)的磷酸化水平下降,提示NGX6基因可能调控EGFR通路,影响NF-κB的活化,影响肿瘤的发生、发展。
在前期研究工作的基础上,结合对NGX6基因生物信息学特征分析的结果,本研究为进一步对NGX6基因功能的探讨做了如下实验：
1.利用已构建好的pcDNA3.1(+)／NGX6／HT-29结肠癌细胞,通过鸡胚绒毛尿囊膜血管(CAM)形成实验,将结肠癌细胞接种到鸡胚绒毛尿囊膜,发现NGX6基因抑制了鸡胚绒毛尿囊膜血管的形成；将结肠癌细胞接种到裸鼠腋前皮下,发现NGX6基因抑制了结肠癌种植瘤的生长,将种植瘤切片分析证实NGX6基因抑制了结肠癌种植瘤内血管的形成,抑制了种植瘤血管内癌栓的形成,并且抑制了结肠癌的转移；RT-PCR实验表明NGX6基因下调了结肠癌细胞及结肠癌种植瘤内VEGF的表达。这些实验结果表明NGX6基因抑制了结肠癌的血管形成,进而影响了肿瘤的发展及转移。
2.通过PI／Annexin-V双染流式细胞仪检测发现,对于在体外培养的结肠癌细胞,转染了NGX6基因的与未转染的比较,凋亡并无差别,基本上全都是正常的活细胞；通过EMSA分析结肠癌细胞核蛋白,转染了NGX6基因的结肠癌HT-29细胞NF-κB激活明显受到抑制；将结肠癌细胞接种到裸鼠腋前皮下,将种植瘤通过PI／Annexin-V双染流式细胞仪检测发现转染了NGX6基因的与未转染的比较,凋亡率明显增高；与化疗药物5-Fu联用后,NGX6基因明显诱导了结肠癌细胞的凋亡。这些实验结果说明NGX6基因通过抑制结肠癌细胞NF-κB的激活,促进了结肠癌细胞的凋亡。
NGX6基因抑制VEGF的表达以及NF-κB的激活间接说明NGX6基因在细胞信号传导中与EGFR信号通路起拮抗作用。本实验说明NGX6基因能抑制肿瘤血管形成以及诱导肿瘤细胞凋亡,此结果为证实NGX6基因是一个抑瘤基因提供一个强有力的证明。结肠癌的侵袭转移是其致命的威胁,本研究中发现NGX6基因抑制了结肠癌的转移,此结果表明NGX6基因对结肠癌患者预后有着积极的影响作用。但是要确定NGX6基因具体的生物学功能以及更为详尽的机制有待以后进一步的研究。
The novel gene NGX6 is isolated by tumor laboratory of Central South University on studying nasopharyngeal carcinoma. NGX6 gene is located on the chromosome 9p21-22. The full-length of NGX6 cDNA is 2134 bp, encoding a polypeptide of 338 amino acids with a predicated molecular weight of 37 kDa. NGX6 protein includes two transmemberane regions. There are an EGF-like domain signature and three potential N-glycosylation sites in the extracellular domain of it. The short cytoplasm contains a tyrosine residue that is a potential phsophorylation site by tyrosine kinase.
Previous study on NGX6 showed:in normal nasopharyngeal epithelial tissues, NGX6 was expressed in high level, while in very low level or undetectable in nasopharyngeal carcinoma biopsies and cell line. NGX6 also be found down-regulated in colorectal carcinomas, and expression of NGX6 was down-regulated in the tumors with metastasis and related to the clinic stages by using the in suit hybridization and tissue array techniques. Transfection of NGX6 into nasopharyngeal and colorectal carcinomas cells can induce the reversion of some malignant phenotypes (data obtained from cell cycle, cell growth rate curve, soft agar colony formation, nude mice injection analysis, et al), the changes of gene/protein expression profiles and the down-regulation of expression of phosphor-EGFR. NGX6 protein mostly is located on cell membrane by using a GFP-NGX6 fusion protein.
NGX6 contains a tyrosine residue that indicate NGX6 maybe influence the cellular signal transduction. And NGX6 contains an EGF-like domain that indicate NGX6 maybe antagonist or work in coordination with proteins with the same construction.
Based on these studies, in an attempt to identify the function of NGX6, we designed the experiments:1. The NGX6-transfected HT-29 cell line was used as the test, empty-vector-transfected HT-29 cell line and untransfected HT-29 cell line were used as the control. The effect of NGX6 in angiogenesis was detected by The CAM experiment and animal model. The CAM experiment and animal model showed the NGX6 gene can inhibite angiogenesis. And the express of VEGF was detected by RT-PCR, that showed the expression of VEGF was down-regulated by NGX6 gene. And there are metastasis in lung of mice were confirmed by hematoxylin-eosin staining Both in PcDNA3.1(+)/HT-29 group and HT-29 group, but there is no found in pcDNA3.1(+)/NGX6/HT-29 group. The NGX6 gene inhibited the metastasis of colon cancer.
2. The effect of NGX6 on Apoptosis was detected by FCM cells were double-stained by PI/Annexin-V. There is no difference of Apoptosis between NGX6 transfected colon carcinoma cells and NGX6 untransfected colon carcinoma cell when cells are cultivated in vitro. But apoptosis level of NGX6 transfected colon carcinoma cells of xenograft tumor in nude mice is higher than that of NGX6 untransfected colon carcinoma cells. The NGX6-transfected HT-29 cell line with 5-Fu was used as the test, HT-29 cell line with 5-Fu and PDTC was used as the control. NGX6 gene obviously enhanced the effects of anti-proliferation and inducing apoptosis of 5-Fu. The express of NF-kB was detected by EMSA. And the express of NF-κB is inhibited in NGX6 transfected colon carcinoma cell groups. These experiments showed NGX6 gene can induce apoptosis of colon cancer and inhibit the expression of NF-κB.
These experiments showed NGX6 gene can inhibite the expression of VEGF and NF-κB. And They also showed that NGX6 gene enhanced the effects of inducing apoptosis and anti-proliferation of colon carcinoma. But it needs more experiments to collect more evidences to understand the exact biological function of NGX6 and its role in the carcinoma.
引文
[1]Vogelstein B, Fearon ER, Hamilton SR, et al. Genetic alterations during colorectal-tumor development. N Engl J Med.1988;319(9):525-532
[2]Fearon, ER, Vogelstein, B. A genetic model for colorectal tumorigenesis. Science,1990,61:759-767.
[3]Baker SJ, Markowitz S, Fearon ER,et al. Suppression of human colorectal ca rcinoma cell growth by wild-type p53. Science.1990;249(4971):912-915.
[4]阳剑波,唐湘娜,邓龙文,等.鼻咽癌染色体9p21-22区域精细缺失图谱的构建.中华肿瘤杂志,1999,21(6)：419-421.
[5]阳剑波,宾亮华,李忠花,等.精细定位和克隆9p21-22区域内鼻咽癌候选抑瘤基因.癌症,2000,19(1)：6-9.
[6]Li J, Tan C, Xiang Q, et al. Proteomic detection of changes in protein synthesis induced by NGX6 transfected in human nasopharyngeal carcinoma cells. J Protein Chem,2001,20(3):265-271.
[7]张晓梅,沈守荣,王晓艳等.胃癌和大肠癌中肿瘤相关基因NGX6的表达.世界华人消化杂志,2002；10(8)：873-876
[8]李江,黄宇琛,张秋红等.鼻咽癌相关基因NGX6对鼻咽癌细胞周期的影响.生命科学研究,2002,6(4)：300-304.
[9]王晓艳,沈守荣,刘华英等.抑瘤基因NGX6对人结肠癌细胞HT-29生长的影响.世界华人消化杂志,2004；2(3)：574-579.
[10]Laborda J. The role of the epidermal growth factor-like protein dlk in cell differentiation. Histopathol,2000,15(1):119-129.
[11]Van Zoelen EJ, Stortelers C, Lenferink AE, et al. The EGF domain: requirements for binding to receptors of the ErbB family.Vitam Horm, 2000,59:99-131.
[12]Appella E, Weber IT, Blasi F. Structure and function of epidermal growth factor-like regions in proteins.FEBS Lett,1988,231(1):1-4.
[13]Wang T, Ward Y, Tian L, et al. CD97, an adhesion receptor on in flammatory cells, stimulates angiogenesis through binding integrin counterrecptors on endothelial cells. Blood,2005,105(7):2833-44.
[14]Fiedler U, krissl T, Koidl S, et al. Angiopoietin-1 and Angiopoietin-2 share the. same binding domains in the Tie-2 receptor involving the first Ig-like loop and the epidermal growth factor-like repeats. J Biol Chem,2003,278(3):1721-7
[15]Alexandre Chlenski, Shuqing Liu, Lisa J. Baker, et al. Neuroblastoma Angiogenesis Is Inhibited with a Folded Synthetic Molecule Corresponding to the Epidermal Growth Factor-Like Module of the Follistatin Domain of SPARC. Cancer Research,2004,64:7420-7425.
[16]Jie JZ, Wang JW, Qu JG, et al. Supression of human colon tumor growth by adenoviral vector-mediated NK4 expression in an athymic mouse model. Word J Gastroenterol,2007,13(13):1938-46. PMID:17461494
[17]Chlenski A, Liu S, Baker LJ, et al. Neuroblastoma Angiogenesis Is Inhibited with a Folded Synthetic Molecule Corresponding to the Epidermal Growth Factor-Like Module of the Follistatin Domain of SPARC. Cancer Res, 2004,64(20):7420-7425.
[18]Wang L, Ma J, Li J, et al. NGX6 gene inhibits cell proliferation and plays a negative role in EGFR pathway in nasopharyngeal carcinoma cells. J Cell Biochem.2005 May 1;95(1):64-73.
[19]Wood burn JR. The epidermal growth factor receptor and its inhibition in cancer therapy.Pharmacol Ther,1999,82(2-3):241-250.
[20]Yu HG, Yu LL, Yang Y, et al. Increased expression of RelA/nuclear factor-kappa B protein correlates with colorectal tumorigenesis. Oncology,2003;65(1):37-45.
[21]Rakitina TV, Vasilevskaya IA, O'Dwyer PJ. Additive interaction of oxaliplatin and 17-allylamino-17-demethoxygeldanamycin in colon cancer cell lines results from inhibition of nuclear factor kappaB signaling. Cancer Res.2003, 15;63(24):8600-5.
[22]Thoms HC, Dunlop MG, Stark la. p38-mediated inactivation of cyclin D1/cyclin-dependent kinase 4 stimulates nucleolar translocation of RelA and apoptosis in colorectal cancer cells. Cancer Res.2007,67(4):1660-9.
[23]Weinder N. Current pathologic methods for measuring intratumoral microvessel density within breast carcinoma and other solid tumors. Breas Cancer Res Treat, 1995,36:169-180.
[24]Kinzler KW, Nilbert MC, Vogelstein B et al. Identification of a gene located at chromosome 5q21 that is mutated in colorectal cancers. Science,1991, 251:1366-1369.
[25]Baker SJ, Fearon ER, Nigro JM et al. Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas. Science,1989,244:217-221.
[26]Fearon ER, Cho KR, Nigro JM et al. Identification of a chromosome 18q gene that is altered in colorectal cancer. Science,247:49-56,1990.
[27]Martignetti JA, Gelb BD, Pierce H, et al. Malignant fibrous histiocytoma: inherited and sporadic forms have loss of heterozygosity at chromosome bands 9p21-22-evidence for a common genetic defect. Genes Chromosomes Cancer, 2000,27(2):191-195.
[28]Kim NG, Kim JJ, Ahn JY, et al. Putative chromosomal deletions on 9p,9q and 22q occur preferentially in malignant gastrointestinal stroma tumors. Int J Cancer,2000,85(5):633-638.
[29]Weber TK, Conroy J, Keitz B, et al. Genome-wide allelotyping indicates increased loss of heterozygosity on 9p and 14q in early age of onset colorectal cancer. Cytogenet Cell Genet,1999,86(2):142-147.
[30]Falls DL. Neuregulins:functions, forms, and signaling strategies. Exp Cell Res, 2003,284(1):14-30.
[31]Ghosh S, Johnson JJ, Sen R, et al. Functional relevance of urinary-type plasminogen activator receptor-alpha3betal integrin association in proteinase regulatory pathway. J Biol Chem,2006,281(19):13021-9
[32]Yoon SY, Lee YJ, Seo JH, et al. uPAR expression under hypoxic conditions depends on iNOS modulated ERK phosphorylation in the MDA-MB-231 breast carcinoma cell line. Cell Res,2006,16(1):75-81
[33]Li H, Soria C, Griscelli F, et al. Amino-terminal fragment of urokinase inhibits tumor cell invasion in vitro and in vivo:respective contribution of the urokinase plasminogen activator receptor-dependent or-independent pathway. Hum Gene Ther,2005, Oct;16(10):1157-67.
[34]Schenk S, Hintermann E, Bilban M, et al. Binding to EGF receptor of a laminin-5 EGF-like fragment liberated during MMP-dependent mammary gland involution. J Cell Biol,2003,161(1):197-209.
[35]Norihiko Nakano, Shigeki Higashiyama, Hiroshi Ohmoto, et al. The N-terminal Region of NTAK/Neuregulin-2 Isoforms Has an Inhibitory Activity on Angiogenesis. J Biol Chem,2004,279(12):11465-11470.
[36]Chlenski A, Liu S, Baker LJ, et al. Neuroblastoma Angiogenesis Is Inhibited with a Folded Synthetic Molecule Corresponding to the Epidermal Growth Factor-Like Module of the Follistatin Domain of SPARC. Cancer Res, 2004,64(20):7420-7425.
[37]Schenk S, Hintermann E, Bilban M, et al. Binding to EGF receptor of a laminin-5 EGF-like fragment liberated during MMP-dependent mammary gland involution. J Cell Biol,2003,161(1):197-209.
[38]Yano A, Fujii Y, Iwai a, et al. Glucocorticoids suppress tumor angiogenesis and in vivo growth of prostate cancer cells. Clin Cancer Res, 2006,12(10):3003-3009.
[39]Lee YS, Lim SS, Shin KH, et al. Anti-angiogenic and anti-tumor activities of 2'-hydroxy-4'-methoxychalcone. Biol Pharm Bull,2006,29(5):1028-1031.
[40]Gouyer V, Fontaine D, Dumont P, et al. Autocrine induction of invasion and metastasis by tumor-assiocisted trypsin inhibitor in human colon cancer cells. Oncogene,2008,27(29):4024-33.
[41]Jie JZ, Wang JW, Qu JG, et al. Supression of human colon tumor growth by adenoviral vector-mediated NK4 expression in an athymic mouse model. Word J Gastroenterol,2007,13(13):1938-46.
[42]Kim ES, Hong SY, Lee HK, et al. Guggulsterone inhibits angiogenesis by blocking STAT3 and VEGF expression in colon cancer cells. Oncol Rep,2008,20(6):1321-2.
[43]Plate KH, Breier G, Weich HA et al. Vascualr endothelial growth factor in human gliomas in vivo. Nature,1992,359:845.
[44]Gasparini G, Harris AL. Clinical inportance of the determination of tumor angiogenesis in breast cancer:much more than a new prognostic tool. J Clin Oncol,1995,13:765.
[45]Sharma Mr, Koltowski L, Ownbey Rt, et al. Angiogenesis-associated protein annexin Ⅱ in breast cancer:Selective expression in invasive breast cancer and contribution to tumor invasion and progression. Exp Mol Pathol,2006 ahead of print
[46]Maeda K, Chung YS, Takatsuka S et al. Tumor angiogenesis and tumor cell proliferation as prognostic indicators in gastric carcinoma. Br J Cancer, 1995,72:319
[47]Zheng H, Tsuneyama K, Cheng C, et al. Expressions of KAI1 and tenascin, microvessel density were closely correlated with liver metastasis of gastrointestinal adenocarcinoma. J Clin Pathol,2007,60(1):50-56.
[48]Roth JM, Caunt M, Cretu A, et al. Inhibition of experimental metastasis by targeting the HUIV26 cryptic epitope in collagen. Am J Pathol,2006,168(5):1576-1586.
[49]Leon H, Parker, Maike Schmidt, et al. The endothelial-cell-derived secreted factor Egfl7 regulates vascular tube formation. Nature,2004,428:754-748.
[50]Folkman J, et al. Luong-term culture of ca;illary endothelial cells. Proc Natt Acad Sci USA,1979,76:5217-5221.
[51]Hebbar M, Peyrat JP. Significance of soluble endothelial molecule E-selection in patients with breast cancer. Int J Biol Makers,2000,15(1):15-21.
[52]Sato Y, Abc M, Tanaka K, et al. Signal transduction and transcriptional regulation of angiogenesis. Adv Exp Med Biol,2000,476:109-115.
[53]Kim HJ, Jang SY, Park JI, et al. Vascular endothelial growth factor induced angiogenic gene therapy in patients with peripheral artery disease. Exp Mol Med,2004,36(4):336-344.
[54]Ikeda Y, Fukuda N, Wada M, et al. Development of angiogenic cell and gene therapy by transplantation of umbilical cord blood with vascular endothelial growth factor gene. Hypertens Res,2004,27(2):119-128.
[55]Kordo Y, Arii S, Mori A, et al. Enhancement of angiogenesis, tumor growth, and metastsis by transfection of VEGF into LOVO human colon cancer line. [J] Clin Cancer Res.2000,6(2):622-630.
[56]Kim SJ, Choi IK, Park KH, et al. Serum vascular endothelial growth factor per platelet count in hepatocellular carcinoma, correlations with clinical parameters and survival. J Clin Oncol,2004,34(4):184-190
[57]Giles FJ, Vose JM, Do KA, et al. Clinical relevance of circulating angiogenic factors in patiente with non-Hodgkin's lymphoma or Hodgkin's lymphoma. Leuk Res,2004,28(6):595-604.
[58]Wong mp, Cheung N, Yuen ST, et al. Vascular endothelial growth factor is up-regulated in the early pre-malignant stage of colorectal tumor progression[J]. In J Cancer,1999,81:845-850.
[59]Terris B, Scoazec JY, Rubbia L, etal. Expression of vascular endothelial growth factor in digestive neuroendocrine tumors [J]. Histopathology, 1998,32(2):133-138.
[60]任学琴,景红,傅佩达血管内皮生长因子和微血管密度与结直肠癌侵袭转移的关系。Jounal of Chinese physician.2004,6(5):582-584.
[61]Kimura Y, Sumiyoshi M, Baba K. Antitumor activities of synthetic and natural stilbenes through antiangiogenic action. Cancer Sci,2008,99(10)2083-96.
[62]Kimura Y, Sumiyoshi M, Taniguchi M, et al. Antitumor and antimetastatic actions of anthrone-C-glucoside, cassialoin isolated from Cassia garrettiana heartwood in colon 26-bearing mice. Cancer Sci,2008,99(11):2336-48.
[63]Fernando NT, Koch M, Rothrock C, et al. Tumor escape from endogenous, extracellular matrix-associated angiogenesis inhibitors by up-regulation of multiple proangiogenic factors. Clin Cancer Res,2008,14(5):1529-39.
[64]Xu L, Cochran DM, Tong RT, et al. Placenta growth factor overexpression inhibits tumor growth, angiogenesis, and metastasis by depleting vascular endothelial growth factor homodimers in orthotopic mouse models. Cancer Res, 2006,66(8):3971-3977
[65]Bouquet C, Lamande N, Brand M, et al. Suppression of angiogenesis, tumor growth, and metastasis by adenovirus-mediated gene transfer of human angiotensinogen. Mol Ther,2006,14(2):175-182..
[66]Koskimaki JE, Karagiannis ED, Rosca EV, et al. Peptides derived from type IV collagen, CXC chemokines, and thrombospondin-1 domain-containing proteins inhibit neovascularization and suppress tumor growth in MDA-MB-231 breast cancer xenografts. Neoplasia.2009,11(12):1285-91.
[67]Vidal O, Metges JP, Elizalde I, et al. High preoperative serum vascular endothelial growth factor levels predict poor-clinical outcome after curative resection of gastric cancer. Br J Surg.2009,96(12):1443-51.
[68]Lee SL, Rouhi P, Dahl Jensen L, et al. Hypoxia-induced pathological angiogenesis mediates tumor cell dissemination, invasion, and metastasis in a zebrafish tumor model. Proc Natl Acad Sci U S A.2009,106(46):19485-90.
[69]Shinkai-K,Akedo-H,Mukai-M,et al.Inhibition of in vitro tumor cell invasion by ginsenoside Rg3. Jpn-J-Cancer-Res.1996; 87(4):357-64
[70]Mochizuki-M,Yoo-YC,Matsuzawa-K,et al.Inhibitory effect of tumor metastasis in mice by saponins, ginsenoside-Rb2,20(R)-and 20(S)-ginsenoside-Rg3, of red ginseng. Biol-Pharm-Bull.1995; 18(9):1197-204.
[71]Xu L, Duda DG, di Tomaso E, et al. Direct evidence that bevacizumab, an anti-VEGF antibody, up-regulates SDF1alpha, CXCR4, CXCL6, and neuropilin 1 in tumors from patients with rectal cancer. Cancer Res.2009,69(20):7905-10.
[72]O'Reilly, M.S., Boehm, T., Shing, Y. et al:Endostatin:an endogeneous inhibitor of angiogenesis and tumor growth. Cell 88:277-285,1997
[73]Angiogenesis and its inhibitors. Jpn J Cancer Chemother.1997,24(11): 1585-1593.
[74]Hardwick JC, Van den Brink GR, Offerhaus GJ, et al. NF-kappaB, p38 MAPK and JNK are highly expressed and active in the stroma of human colonic adenomatous polyps. Oncogene.2001,15;20(7):819-27.
[75]Edelblum KL, Goettel JA, Koyama T, et al. TNFR1 promotes tumor necrosis factor-mediated mouse colon epithelial cell survival through RAF activation of NF-kappaB.J Biol Chem.2008,283(43):29485-29494.
[76]Yu HG, Yu LL, Yang Y, et al. Increased expression of RelA/nuclear factor-kappa B protein correlates with colorectal tumorigenesis. Oncology,2003;65(1):37-45.
[77]Higai K, Ishihara S, Matsumoto K. NFkappaB-p65 dependent transcriptional regulation of glycosyltransferases in human colon adenocarcinoma HT-29 by stimulation with tumor necrosis factor alpha. Biol Pharm Bull. 2006,29(12):2372-7.
[78]Chen GG, Lee JF, Wang SH, et al. Apoptosis induced by activation of peroxisome-proliferator activated receptor-gamma is associated with Bcl-2 and NF-kappaB in human colon cancer. Life Sci.2002,70(22):2631-46.
[79]Scaife CL, Kuang J, Wills JC, et al. Nuclear factor kappaB inhibitors induce adhesion-dependent colon cancer apoptosis:implications for metastasis. Cancer Res.2002,62(23):6870-8.
[80]Uetsuka H, Haisa M, Kimura M, et al. Inhibition of inducible NF-kappaB activity reduces chemoresistance to 5-fluorouracil in human stomach cancer cell line. Exp Cell Res,2003,289:27-35
[81]Williams JL, Nath N, Chen J, et al. Growth inhibition of human colon cancer cells by nitric oxide (NO)-donating aspirin is associated with cyclooxygenase-2 induction and beta-catenin/T-cell factor signaling, nuclear factor-kappaB, and NO synthase 2 inhibition:implications for chemoprevention. Cancer Res.2003, 63(22):7613-8.
[82]Fryst H, Oskouian B, Bandhuvula P, et al. Natural sphingadienes inhibit Akt-dependent signaling and prevent intestinal tumorigenesis. Cancer Res. 2009,69(24):9457-9464.
[83]Oraldi M, Trombetta A, biasi F, et al. Decreased polyunsaturated Fatty Acid content contributes to increased survival in human colon cancer. J Oncol.2009, 63(22):7613-8.
[84]Cheung KL, Khor TO, Huang MT,et al. Cancer chemoprevention of azoxymethane/dextran sodium sulfate-induced colon carcinogenesis by phenethyl isothiocyanate and dibenzoylmethane. Carcinogenesis.2009, 14(11):1341-51.
[85]Subauste MC, Ventura-Holman T, Du L,et, al. RACK1 downregulates levels of the pro-apoptotic protein Femlb in apoptosis-resistant colon cancer cells. Cancer Biol Ther.2009,8(23):2297-2305.
[86]Chiou SK, Hoa N. Up-regulation of GADD45alpha expression by NSAIDs leads to apoptotic and necrotic colon cancer cell deaths. Apoptosis. 2009,14(11):1341-51.
[87]Glauben R, Batra A, Stroh T, et al. Histone deacetylases:novel targets for prevention of colitis-associated cancer in mice. Gut.2008,57(5):613-622.
[88]Zhang C, Kolb A, Mattern J, et al. Dexamethasone desensitizes hepatocellular and colorectal tumours toward cytotoxic therapy. Cancer Lett,2006, 242(1):104-111.
[89]Jyoti B, Carlic K, Venkatesh D, et al. Novel retinoic acid metabolism blocking agents endowed with multiple biological activities are efficient growth inhibitors of human breast and prostate cancer cells in vitro and a human breast tumor xenograft in nude mice. J Med Chem,2004,47(27):6716-6729.
[90]Cho SJ, Kim JS, Kim JM, et al. Simvastatin induces apoptosis in human colon cancer cells and in tumor xenografts, and attenuates colitis-associated colon cancer in mice. Int J Cancer.2008,123(4):951-957.
[91]Voboril R, Hochwald SN, Li J, et al. Inhibition of NF-kappa B augments sensitivity to 5-fluorouracil/folinic acid in colon cancer. J Surg Res, 2004,120(2):178-188.
[92]Wood burn JR. The epidermal growth factor receptor and its inhibition in cancer therapy.Pharmacol Ther,1999,82(2-3):241-250.
[93]Boots AW, Hristova M, Kasahara DI, et al. ATP-mediated activation of the NADPH oxidase DUOX1 mediates airway epithelial responses to bacterial stimuli. J Biol Chem.2009,284(26):17858-17867.
[94]Dudek AZ, Lesniewski-Kmak K, Shehadeh NJ, et al. Phase Ⅰ study of bortezomib and cetuximab in patients with solid tumours expressing epidermal growth factor receptor. Br J Cancer.2009,100(9):1379-1384.
[95]Gadgeel SM, Ali S, Philip PA, et al. Genistein enhances the effect of epidermal growth factor receptor tyrosine kinase inhibitors and inhibits nuclear factor kappa B in nonsmall cell lung cancer cell lines. Cancer. 2009,115(10):2165-2176.
[96]Shant J, Cheng K, Marasa BS, et al. Akt-dependent NF-kappaB activation is required for bile acids to rescue colon cancer cells from stress-induced apoptosis. Exp Cell Res.2009,315(3):432-450.
[97]Suh Y, Afaq F, Johnson JJ, et al. A plant flavonoid fisetin induces apoptosis in colon cancer cells by inhibition of COX2 and Wnt/EGFR/NF-kappaB-signaling pathways. Carcinogenesis.2009,30(2):300-307.
[98]Huang L, Verstrepen L, Heyninck K, et al. ABINs inhibit EGF receptor-mediated NF-kappaB activation and growth of EGF receptor-overexpressing tumour cells. Oncogene.2008,27(47):6131-6140.
[99]Ray RM, Bhattacharya S, Johnson LR. EGFR plays a pivotal role in the regulation of polyamine-dependent apoptosis in intestinal epithelial cells. Cell Signal.2007,19(12):2519-2527.
[100]Cascinu S, Berardi R, Salvagni S, et al. A combination of gefitinib and FOLFOX-4 as first-line treatment in advanced colorectal cancer patients. A GISCAD multicentre phase II study including a biological analysis of EGFR overexpression, amplification and NF-kB activation. Br J Cancer. 2008,98(1):71-76.
[101]Iljin K, Karkkanen MJ, Lawrence EC, et al.VEGFR3 gene structure, regulatory region,and sequence polymorphisms [J].FASEB J,2001,15:1028-1036
[102]Hamada T, Ui-Tei K, Miyata Y. A novel gene derived frim developing spinal cords SCDGF, is a unique member of the PDGF/VEGF family [J]. FEBS Lett, 2000,475(2):97-102.
[103]Siemeister G, Marting BG. The alpha-helical domain near the amino terminus is essential for dimerization of vascular endothelial growth factor [J].J Biol Chem,1998,273(18):1115-11120.
[104]Waltenberger J, Claessen EL, Siegbahn A, et al. Different signal transduction properties of KDRand Fltl, two receptors for vascular endothelial grwth factor [J].J Biol Chem,1994,269,(43):2698-2699.
[105]Brown LF,lanir N, McDonagh J, et al. Fbrioblast migration in fibrin gel matrices[J]. Am J Pathol,1993142(1):273-283.
[106]Kubo H, Fujiwara T, L, Invlvement of vascular endothelial growth:factor receptor-3 in maintenance of integrity of endothelial cell lining during tumor angiogenesis[J]. Blood,2004,96(2):546-53.
[107]Gospodarowicz D, Localisation of a fibroblast growth factor and its Effect alone with hydrocortisone on 3T3 cell growth. Nature.1974,249(453):123-129
[108]Zeytin FN, Rusk SF, Baird A, et al. Induction of c-fos, calcitonin gene expression, and acidic fibroblast growth factor production in a multipeptide- secreting neuroendocrine cell line. Endocrinology.1988 Mar; 122(3):1114-1120
[109]Dirix LY, Vermeulen PB, Pawinski A, et al. Elevated levels of the angiogenic cytokines basic fibroblast growth factor and vascular endothelial growth factor in sera of cancer patients. Br J Cancer.1977,76(2):238-243
[110]Davis S, Aldrich TH, Jones PF, et al. Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by Secretion-Trap expression cloing. Cell,1996,87(7):1161-1170
[111]Maisonpierre PC, Suri C, Jones PF, et al. Angiopoietin-2, a natural antiagonist for tie2 that disrupt in vivo angiogenesis. Science,1997,277(5322):55-60
[112]Valenzuela DM, Griffiths JA, Rojas J, et al. Angiopoietins 3 and 4:Diverging gene counterparts in mice and humans. Proc Natl Acad Sci USA,1999, 96(5):1904-1909
[113]Lee JH, Koh JT, Shin BA, et al. Comparative study of angiostatic and anti-invasive gene expressions as prognostic factors in gastric cancer[J]. Oncol, 2001,18(2):355-61
[114]Syed A Ahmad, Wenbiao Liu, Yong D Jung, etal. The effects of angiopoietin-1 and 2 on tumor growth ang angiogenesis in human colon cancer. Cancer Res, 2001,61:1255-1259
[115]Anne Saaristo, Terhi Karpanen, Kari Alitalo. Mechanisms of angiogenesis and their use in the inhibitions of tumor growth and metastasis. Oncogene, 2000,19:6122-6129
[116]Ahmad SA, Liu W, Jung YD, et al. Differential expression of angiopoietin-1and angiopoietin-2 in colon carcinoma. Cancer,2001,92(5):1138-1143
[117]Etoh T, Inoue H, Tanaka S, et al. Angiopoietin-2 is related to tumor angiogenesis in gastric carcinoma:possible in vivo regulation via induction of proteases. Cancer Res,2110,61(5):2145-2153
[118]Tanaka S, Sugimachi K, Yamashita Yi Y, et al. Tie2 vascular endothelial receptor expression and function in hepatocellular carcinoma. Hepathology, 2002,35(4):861-867
[119]Furukawa T, Yoshimura A, Sumizawa T, et al. Angiogenic factor. Nature,356:668
[120]Stevenson DP, Milligan SR, Collins WP, et al. Effects of platelet-derived endothelial cell growth factor/thymidine phosphorlase, substrate, and products in three-dimensional model of angiogenesis. AJP,1998,152:1641-1646
[121]Pujimoto K, Hosotaoi R, Wada M, et al. Expression of two angiogenic factors, vascular endothelial growth factor and platelet derived endothelial growth factor in human pancreafic cancer, and its relationship to angiogenesis. Eur J Cancer, 1998,34(9):1439-1447
[122]Takao S, Takebeyashi Y, Che X, et al. Expression of thymidine phosphorylase is associated with a poor progrosis in patients with ductal adenocarcinoma of the pancreas. Clin Cancer Res,1998,4(7):1619-1624
[123]Zelinski DP, Zantek ND, Stewart J C, et al. EphA2 over-expression causes tumorgenesis of mammary epithelial cells[J]. Cancer,2001,61(9):2301-2306.
[124]Liu W, Ahmad SA, Jung YD, et al. Coexpression of EphrinBs and receptors in colon carcinoma[J]. Cancer,2002,94(4):934-939.
[125]Brantley DM, Chen N, Thompson EJ, et al. Soluble EphA receptors inhibit tumor angiogenesis and progression in vivo[J]. Oncogene,2002,21(46): 7011-7026.
[126]Zhong H, De-Marzo AM, Laughner E, et al. Overexpression of hypoxia-inducible-factor-1 alpha in common human cancers and their metastasis. Cancer Res,1999,59:5830-5835.
[127]Sivridis E, Giatromanolaki A, Gatter KC, et al. Association of hypoxia-inducible-factor-1 alpha and 2alpha with activated angiogenic pathways and prognosis in pations with endometrial carcinoma. Cancer, 2002,95(5):1055-1064
[128]Carmeliet P, Dor Y, Hewbert JM, et al. Role of HIF-1 alpha in hypoxia-nediated apoptosis, cell proliferation ang tumor angiogenesis. Nature,1998,394:485-490.
[129]O'reilly MS, Holmgren L, Shin Y, et al. Angiostatin:a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell.1994;79:315-328.
[130]Stathakis P, Fitzgerald M,Lisa J, et al. Generation of Angiostatin by reduction and proteolysis of Plasmin [J].J biolog chemi,1997,272(33):20641-20645.
[131]Welsh CL, Welsh, Ito B, et al. Angiostatin induces endothelial cell apoptosis and activation of focal adhesion kinase independently of the integrin-binding motif RGD. Proc Natl Acad Sci U.S.A.1998;95:5579-5583.
[132]Yihai Cao, Richard WJi, Dong Davidson, et al. Kringle domains of Human Angiostatin [J]. The Journal of biological chemistry,1996,271(46):29461-29467.
[133]Yihai Cao, Andrew Chen, Seong Soo A, et al. Kringle 5 of Plasminogen is a Novel Inhibitor of Endothelial Cell Growth [J].The journal of biological chemistry,1997,272(36):22924-22928.
[134]Hanaha D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis [J]. Cell,1996,86:353-364.
[135]Yihai Cao, Michael S, O'Reilly, et al. Expression of angiostatin cDNA in a Murine fibrosarcoma suppresses primary tumor growth and produces long-term dormancy of metastases [J]. J Clin Invest,1998,101(5):1055-1063.
[136]Gupta N, Nodzenski E, Khodarev NN, et al. Angiostatin effects on endothelial cells mediated by ceramide and RhoA. EMBO,2001,2(6):536-540
[137]Moser TL, Kenan DJ, Ashley TA, et al. Endothelial cell surface F1-F0 ATP synthase is active in ATP synthesis and is inhibited by angiostatin. Proc Natl Acad Sci USA,2001,98(12):6656-6661.
[138]Jiang L, Jha V, Dhanabal M, et al. Intracellular Ca(2) signaling in endothelial cells by the angiogenesis inhibitors endostatin and angiostatin. Am J Physiol Cell Physiol,2001,280(5):1140-1150
[139]Rony S, Edwin GK. The MAPK signaling cascade. FASEB,1995,9:726-735.
[140]O'Reilly MS, Boehm T, Shing Y, et al. Endostatin:an endogenous inhibitor of angiogenesis and tumor growth. Cell,1997,88(2):277-85
[141]Blezinger P, Wang J, Gondo m, et al. Systemic inhibitor of tumor growth and tumor metastasis by intramuscular administration of the enstatin gene. Nat Bio Technol,1999,17(4):343-349.
[142]Youngmi K, Jinwook J, Ok Hee J, et al. Endostatin inhibits endothelial and tumorcellular invasion by blocking the activation and catalytic of matrix metalloproteinase 2. Cancer Res,2000,60:5410-5413.
[143]MOhanraj D, Ramami R, Ruediger V, et al. Endostatin:Yeast production, mutant, and antitumor effect in renal cell carcinoma. Cancer Res, 1999,39:189-197.
[144]Yokoyama Y, Dhamabal M, Griffioen Aw, et al. Synergy between angiostatin and endostatin:inhibition of overian cancer growth. Cancer Res,2000,60: 2190-2196
[145]Perletti A, concari P, Giardini R, et al. Antitumor activity of endostatin against carcinogen-induced rat primary mammary tumor. Cancer Res,2000,61: 1793-1796.
[146]Kirsh M, Schackert G, Black PM. Anti-angiogenic treatment strategies for malignant brain tumor. J Neurooncol,2000,50:149-163.
[147]Mohanraj Dhanabal, Ramani Ramchandran,et al. Endostatin Induces Endothelial Cell Apoptosis.J Biol Chem,1999,274(17):11721-11726.
[148]Johan Dixelius, Helena Larsson Endostatin-induced tyrosine kinase signaling through the Shb adaptor protein regulates endothelial cell apoptosis.Blood, 2000,95(11):3403-3411.
[149]Rehn M, Veikkola T, Kukk Valdre E, et al.Interaction of endostatinwith integrins implicated in angiogenesis.Proc Natl Acad Sci USA,2001,98 (3):1024-1029.
[150]Shichiri M, Hirata Y.Antiangiogenesisignals by endostatin.FASEB J,2001,15 (6):1044-1053.
[151]Donald R. Senger, Kevin P. Claffey, et al. Angiogenesis promoted by vascular endothelial growth factor:Regulation through 11 and 21 integrins. Proc. Natl. Acad. Sci. USA.1997,94(25):13612-13617.
[152]Hayyes AJ, Li LY, Lippman ME. Antivascular therapy:a new approach to cancer treatment. BMJ,1999,318(7187):853-855
[153]Jimyenez B, Volpert OV, Crawford SE, et al. Signals leading to apoptosis-dependent inhibition of neovascularization by thrombospondin. Nat Med,2000,6(1):41-48.
[154]Bleuel K, Popp S, Fusenig NE, et al. Tumor suppression in human skin carcinoma cells by chromosome 15 transfer or thrombospondin-1 overexpression through halted tumor vascularization. Proc Natl Acad Sci USA, 1999,96(5):2065-2070.
[155]Narazaki M, Tosato G. Canstatin:an inhibitor of angiogenesis and tumor growth revisited. Cancer J 2006; 12:110-112
[156]Kamphaus GD, Colorado PC, Panka DJ, Hopfer H, Ramchandran R, Torre A, Maeshima Y, Mier JW, Sukhatme VP, Kalluri R. Canstatin, a novel matrix-derived inhibitor of angiogenesis and tumor growth. J Biol Chem 2000; 275:1209-1215
[157]Kamphaus GD, Colorado PC, Panka DJ, et al. Canstatin, a novel matrix-derived inhibitor of angiogenesis and tumor growth. J Biol Chem, 2000,275(2):1209-1215
[158]Sen R, Baltimore D. Inducibility of the immunoglobulin enhancer-binding protein NF-KB by a posttranslational mechaniam. Cell,1986,47:921-928
[159]Baeuerle PA,Henkel T. Function and activation of NF-kappa B in the immune system[J]. Annu Rev Immunol,1994,12:141-179
[160]Baeuerle PA, Baltimore D. NF-kappa B:ten years after. Cell.199687(1):13-20.
[161]Christman JW, Sadikot RT, Blackwell TS. The role of nuclear factor-kappa B in pulmonary diseases. Chest.2000,117(5):1482-7.
[162]Beg AA, Sha WC, Bronson RT,et al. Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-kappa B. [J]. Nature, 1995,376 (6536)::167-170.
[163]Iimuro Y,Nishiura T,Hellerbrand C,et al. NFkappaB prevents apoptosis and liver dysfunction during liver regeneration. [J]. J Clin Invest,1998,101: 802-811.
[164]Wang CY, Mayo MW, Baldwin AS. TNF-and cancer therapy-induced apoptosis: potentiation by inhibition of NF-kappaB. [J]. Science,1996,274:784-787.
[165]Wang CY,Guttridge DC,Mayo MW,et al. NF-kappa B induces expression of the Bcl22 homologue Al/Bfl-1 to preferentially suppresschemotherapy-induced apoptosis[J].Mol Cell Biol,1999,19:5923-59291
[166]Lee HH,Dadgostar H,Cheng Q,et al. NF-kappa B-mediated up-regulation of Bcl-x and Bfl/Al is required for CD40 survival signaling in B lymphocytes[J]. Proc Natl Acad Sci USA,1999,96:9136-91411
[167]Wang CY,Mayo MW,Korneluk RG,et al. NF-kappa B antiapoptosis:induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 tosuppress caspase-8 activation [J]. Science,1999,281:1680-16831
[168]Wu MX,Ao Z,Prasad KV,et al. IEX-1L,an apoptosis inhibitor involved in NF-kappa B-mediated cell survival [J]. Science,1999,281:998-10011
[169]Bushdid PB, Brantley DM, Yull FE, et al. Inhibition of NF-kappaB activity results in disruption of the apical ectodermal ridge and aberrant limb morphogenesis. Nature,1998,9;392(6676):615-8.
[170]Hardwick JC, Van den Brink GR, Offerhaus GJ, et al. NF-kappaB, p38 MAPK and JNK are highly expressed and active in the stroma of human colonic adenomatous polyps. Oncogene.2001,15;20(7):819-27.
[171]Yu HG, Yu LL, Yang Y, et al. Increased expression of RelA/nuclear factor-kappa B protein correlates with colorectal tumorigenesis. Oncology,2003;65(1):37-45.
[172]Lee DK, Park SY, Baik SK, et al. Deoxycholic acid-induced signal transduction in HT-29 cells:role of NF-kappa B and interleukin-8. Korean J Gastroenterol. 2004,43(3):176-85.
[173]Chen GG, Lee JF, Wang SH, et al. Apoptosis induced by activation of peroxisome-proliferator activated receptor-gamma is associated with Bcl-2 and NF-kappaB in human colon cancer. Life Sci.2002,70(22):2631-46.
[174]Scaife CL, Kuang J, Wills JC, et al. Nuclear factor kappaB inhibitors induce adhesion-dependent colon cancer apoptosis:implications for metastasis. Cancer Res.2002,62(23):6870-8.
[175]Uetsuka H, Haisa M, Kimura M, et al. Inhibition of inducible NF-kappaB activity reduces chemoresistance to 5-fluorouracil in human stomach cancer cell line. Exp Cell
[176]Williams JL, Nath N, Chen J, et al. Growth inhibition of human colon cancer cells by nitric oxide (NO)-donating aspirin is associated with cyclooxygenase-2 induction and beta-catenin/T-cell factor signaling, nuclear factor-kappaB, and NO synthase 2 inhibition:implications for chemoprevention. Cancer Res.2003, 63(22):7613-8
[177]Rakitina TV, Vasilevskaya IA, O'Dwyer PJ. Additive interaction of oxaliplatin and 17-allylamino-17-demethoxygeldanamycin in colon cancer cell lines results from inhibition of nuclear factor kappaB signaling. Cancer Res.2003, 15;63(24):8600-5.
[178]Din FV, Dunlop MG, Stark LA. Evidence for colorectal cancer cell specificity of aspirin effects on NF kappa B signalling and apoptosis. Br J Cancer.2004, 91(2):381-8.
[179]Higai K, Ishihara S, Matsumoto K. NFkappaB-p65 dependent transcriptional regulation of glycosyltransferases in human colon adenocarcinoma HT-29 by stimulation with tumor necrosis factor alpha. Biol Pharm Bull. 2006,29(12):2372-7.
[180]Thorns HC, Dunlop MG, Stark la. p38-mediated inactivation of cyclin Dl/cyclin-dependent kinase 4 stimulates nucleolar translocation of RelA and apoptosis in colorectal cancer cells. Cancer Res.2007,67(4):1660-9
[181]Yu HG, Yu LL, Yang Y, et al. Increased expression of RelA/nuclear factor-kappa B protein correlates with colorectal tumorigenesis. Oncology,2003;65(1):37-45.
[182]Lee DK, Park SY, Baik SK, et al. Deoxycholic acid-induced signal transduction in HT-29 cells:role of NF-kappa B and interleukin-8. Korean J Gastroenterol. 2004,43(3):176-85.
[183]Chen GG, Lee JF, Wang SH, et al. Apoptosis induced by activation of peroxisome-proliferator activated receptor-gamma is associated with Bcl-2 and NF-kappaB in human colon cancer. Life Sci.2002,70(22):2631-46.
[184]Scaife CL, Kuang J, Wills JC, et al. Nuclear factor kappaB inhibitors induce adhesion-dependent colon cancer apoptosis:implications for metastasis. Cancer Res.2002,62(23):6870-8.
[185]Uetsuka H, Haisa M, Kimura M, et al. Inhibition of inducible NF-kappaB activity reduces chemoresistance to 5-fluorouracil in human stomach cancer cell line. Exp Cell
[186]Williams JL, Nath N, Chen J, et al. Growth inhibition of human colon cancer cells by nitric oxide (NO)-donating aspirin is associated with cyclooxygenase-2 induction and beta-catenin/T-cell factor signaling, nuclear factor-kappaB, and NO synthase 2 inhibition:implications for chemoprevention. Cancer Res.2003, 63(22):7613-8
[187]Rakitina TV, Vasilevskaya IA, O'Dwyer PJ. Additive interaction of oxaliplatin and 17-allylamino-17-demethoxygeldanamycin in colon cancer cell lines results from inhibition of nuclear factor kappaB signaling. Cancer Res.2003, 15;63(24):8600-5.
[188]Voboril R, Hochwald SN, Li J, et al. Inhibition of NF-kappa B augments sensitivity to 5-fluorouracil/folinic acid in colon cancer. J Surg Res, 2004,120(2):178-188.
[189]Din FV, Dunlop MG, Stark LA. Evidence for colorectal cancer cell specificity of aspirin effects on NF kappa B signalling and apoptosis. Br J Cancer.2004, 91(2):381-8.
[190]Higai K, Ishihara S, Matsumoto K. NFkappaB-p65 dependent transcriptional regulation of glycosyltransferases in human colon adenocarcinoma HT-29 by stimulation with tumor necrosis factor alpha. Biol Pharm Bull. 2006,29(12):2372-7.
[2]Fearon, ER, Vogelstein, B. A genetic model for colorectal tumorigenesis. Science,1990,61:759-767.
[3]Baker SJ, Markowitz S, Fearon ER,et al. Suppression of human colorectal ca rcinoma cell growth by wild-type p53. Science.1990;249(4971):912-915.
[4]阳剑波,唐湘娜,邓龙文,等.鼻咽癌染色体9p21-22区域精细缺失图谱的构建.中华肿瘤杂志,1999,21(6)：419-421.
[5]阳剑波,宾亮华,李忠花,等.精细定位和克隆9p21-22区域内鼻咽癌候选抑瘤基因.癌症,2000,19(1)：6-9.
[6]Li J, Tan C, Xiang Q, et al. Proteomic detection of changes in protein synthesis induced by NGX6 transfected in human nasopharyngeal carcinoma cells. J Protein Chem,2001,20(3):265-271.
[7]张晓梅,沈守荣,王晓艳等.胃癌和大肠癌中肿瘤相关基因NGX6的表达.世界华人消化杂志,2002；10(8)：873-876
[8]李江,黄宇琛,张秋红等.鼻咽癌相关基因NGX6对鼻咽癌细胞周期的影响.生命科学研究,2002,6(4)：300-304.
[9]王晓艳,沈守荣,刘华英等.抑瘤基因NGX6对人结肠癌细胞HT-29生长的影响.世界华人消化杂志,2004；2(3)：574-579.
[10]Laborda J. The role of the epidermal growth factor-like protein dlk in cell differentiation. Histopathol,2000,15(1):119-129.
[11]Van Zoelen EJ, Stortelers C, Lenferink AE, et al. The EGF domain: requirements for binding to receptors of the ErbB family.Vitam Horm, 2000,59:99-131.
[12]Appella E, Weber IT, Blasi F. Structure and function of epidermal growth factor-like regions in proteins.FEBS Lett,1988,231(1):1-4.
[13]Wang T, Ward Y, Tian L, et al. CD97, an adhesion receptor on in flammatory cells, stimulates angiogenesis through binding integrin counterrecptors on endothelial cells. Blood,2005,105(7):2833-44.
[14]Fiedler U, krissl T, Koidl S, et al. Angiopoietin-1 and Angiopoietin-2 share the. same binding domains in the Tie-2 receptor involving the first Ig-like loop and the epidermal growth factor-like repeats. J Biol Chem,2003,278(3):1721-7
[15]Alexandre Chlenski, Shuqing Liu, Lisa J. Baker, et al. Neuroblastoma Angiogenesis Is Inhibited with a Folded Synthetic Molecule Corresponding to the Epidermal Growth Factor-Like Module of the Follistatin Domain of SPARC. Cancer Research,2004,64:7420-7425.
[16]Jie JZ, Wang JW, Qu JG, et al. Supression of human colon tumor growth by adenoviral vector-mediated NK4 expression in an athymic mouse model. Word J Gastroenterol,2007,13(13):1938-46. PMID:17461494
[17]Chlenski A, Liu S, Baker LJ, et al. Neuroblastoma Angiogenesis Is Inhibited with a Folded Synthetic Molecule Corresponding to the Epidermal Growth Factor-Like Module of the Follistatin Domain of SPARC. Cancer Res, 2004,64(20):7420-7425.
[18]Wang L, Ma J, Li J, et al. NGX6 gene inhibits cell proliferation and plays a negative role in EGFR pathway in nasopharyngeal carcinoma cells. J Cell Biochem.2005 May 1;95(1):64-73.
[19]Wood burn JR. The epidermal growth factor receptor and its inhibition in cancer therapy.Pharmacol Ther,1999,82(2-3):241-250.
[20]Yu HG, Yu LL, Yang Y, et al. Increased expression of RelA/nuclear factor-kappa B protein correlates with colorectal tumorigenesis. Oncology,2003;65(1):37-45.
[21]Rakitina TV, Vasilevskaya IA, O'Dwyer PJ. Additive interaction of oxaliplatin and 17-allylamino-17-demethoxygeldanamycin in colon cancer cell lines results from inhibition of nuclear factor kappaB signaling. Cancer Res.2003, 15;63(24):8600-5.
[22]Thoms HC, Dunlop MG, Stark la. p38-mediated inactivation of cyclin D1/cyclin-dependent kinase 4 stimulates nucleolar translocation of RelA and apoptosis in colorectal cancer cells. Cancer Res.2007,67(4):1660-9.
[23]Weinder N. Current pathologic methods for measuring intratumoral microvessel density within breast carcinoma and other solid tumors. Breas Cancer Res Treat, 1995,36:169-180.
[24]Kinzler KW, Nilbert MC, Vogelstein B et al. Identification of a gene located at chromosome 5q21 that is mutated in colorectal cancers. Science,1991, 251:1366-1369.
[25]Baker SJ, Fearon ER, Nigro JM et al. Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas. Science,1989,244:217-221.
[26]Fearon ER, Cho KR, Nigro JM et al. Identification of a chromosome 18q gene that is altered in colorectal cancer. Science,247:49-56,1990.
[27]Martignetti JA, Gelb BD, Pierce H, et al. Malignant fibrous histiocytoma: inherited and sporadic forms have loss of heterozygosity at chromosome bands 9p21-22-evidence for a common genetic defect. Genes Chromosomes Cancer, 2000,27(2):191-195.
[28]Kim NG, Kim JJ, Ahn JY, et al. Putative chromosomal deletions on 9p,9q and 22q occur preferentially in malignant gastrointestinal stroma tumors. Int J Cancer,2000,85(5):633-638.
[29]Weber TK, Conroy J, Keitz B, et al. Genome-wide allelotyping indicates increased loss of heterozygosity on 9p and 14q in early age of onset colorectal cancer. Cytogenet Cell Genet,1999,86(2):142-147.
[30]Falls DL. Neuregulins:functions, forms, and signaling strategies. Exp Cell Res, 2003,284(1):14-30.
[31]Ghosh S, Johnson JJ, Sen R, et al. Functional relevance of urinary-type plasminogen activator receptor-alpha3betal integrin association in proteinase regulatory pathway. J Biol Chem,2006,281(19):13021-9
[32]Yoon SY, Lee YJ, Seo JH, et al. uPAR expression under hypoxic conditions depends on iNOS modulated ERK phosphorylation in the MDA-MB-231 breast carcinoma cell line. Cell Res,2006,16(1):75-81
[33]Li H, Soria C, Griscelli F, et al. Amino-terminal fragment of urokinase inhibits tumor cell invasion in vitro and in vivo:respective contribution of the urokinase plasminogen activator receptor-dependent or-independent pathway. Hum Gene Ther,2005, Oct;16(10):1157-67.
[34]Schenk S, Hintermann E, Bilban M, et al. Binding to EGF receptor of a laminin-5 EGF-like fragment liberated during MMP-dependent mammary gland involution. J Cell Biol,2003,161(1):197-209.
[35]Norihiko Nakano, Shigeki Higashiyama, Hiroshi Ohmoto, et al. The N-terminal Region of NTAK/Neuregulin-2 Isoforms Has an Inhibitory Activity on Angiogenesis. J Biol Chem,2004,279(12):11465-11470.
[36]Chlenski A, Liu S, Baker LJ, et al. Neuroblastoma Angiogenesis Is Inhibited with a Folded Synthetic Molecule Corresponding to the Epidermal Growth Factor-Like Module of the Follistatin Domain of SPARC. Cancer Res, 2004,64(20):7420-7425.
[37]Schenk S, Hintermann E, Bilban M, et al. Binding to EGF receptor of a laminin-5 EGF-like fragment liberated during MMP-dependent mammary gland involution. J Cell Biol,2003,161(1):197-209.
[38]Yano A, Fujii Y, Iwai a, et al. Glucocorticoids suppress tumor angiogenesis and in vivo growth of prostate cancer cells. Clin Cancer Res, 2006,12(10):3003-3009.
[39]Lee YS, Lim SS, Shin KH, et al. Anti-angiogenic and anti-tumor activities of 2'-hydroxy-4'-methoxychalcone. Biol Pharm Bull,2006,29(5):1028-1031.
[40]Gouyer V, Fontaine D, Dumont P, et al. Autocrine induction of invasion and metastasis by tumor-assiocisted trypsin inhibitor in human colon cancer cells. Oncogene,2008,27(29):4024-33.
[41]Jie JZ, Wang JW, Qu JG, et al. Supression of human colon tumor growth by adenoviral vector-mediated NK4 expression in an athymic mouse model. Word J Gastroenterol,2007,13(13):1938-46.
[42]Kim ES, Hong SY, Lee HK, et al. Guggulsterone inhibits angiogenesis by blocking STAT3 and VEGF expression in colon cancer cells. Oncol Rep,2008,20(6):1321-2.
[43]Plate KH, Breier G, Weich HA et al. Vascualr endothelial growth factor in human gliomas in vivo. Nature,1992,359:845.
[44]Gasparini G, Harris AL. Clinical inportance of the determination of tumor angiogenesis in breast cancer:much more than a new prognostic tool. J Clin Oncol,1995,13:765.
[45]Sharma Mr, Koltowski L, Ownbey Rt, et al. Angiogenesis-associated protein annexin Ⅱ in breast cancer:Selective expression in invasive breast cancer and contribution to tumor invasion and progression. Exp Mol Pathol,2006 ahead of print
[46]Maeda K, Chung YS, Takatsuka S et al. Tumor angiogenesis and tumor cell proliferation as prognostic indicators in gastric carcinoma. Br J Cancer, 1995,72:319
[47]Zheng H, Tsuneyama K, Cheng C, et al. Expressions of KAI1 and tenascin, microvessel density were closely correlated with liver metastasis of gastrointestinal adenocarcinoma. J Clin Pathol,2007,60(1):50-56.
[48]Roth JM, Caunt M, Cretu A, et al. Inhibition of experimental metastasis by targeting the HUIV26 cryptic epitope in collagen. Am J Pathol,2006,168(5):1576-1586.
[49]Leon H, Parker, Maike Schmidt, et al. The endothelial-cell-derived secreted factor Egfl7 regulates vascular tube formation. Nature,2004,428:754-748.
[50]Folkman J, et al. Luong-term culture of ca;illary endothelial cells. Proc Natt Acad Sci USA,1979,76:5217-5221.
[51]Hebbar M, Peyrat JP. Significance of soluble endothelial molecule E-selection in patients with breast cancer. Int J Biol Makers,2000,15(1):15-21.
[52]Sato Y, Abc M, Tanaka K, et al. Signal transduction and transcriptional regulation of angiogenesis. Adv Exp Med Biol,2000,476:109-115.
[53]Kim HJ, Jang SY, Park JI, et al. Vascular endothelial growth factor induced angiogenic gene therapy in patients with peripheral artery disease. Exp Mol Med,2004,36(4):336-344.
[54]Ikeda Y, Fukuda N, Wada M, et al. Development of angiogenic cell and gene therapy by transplantation of umbilical cord blood with vascular endothelial growth factor gene. Hypertens Res,2004,27(2):119-128.
[55]Kordo Y, Arii S, Mori A, et al. Enhancement of angiogenesis, tumor growth, and metastsis by transfection of VEGF into LOVO human colon cancer line. [J] Clin Cancer Res.2000,6(2):622-630.
[56]Kim SJ, Choi IK, Park KH, et al. Serum vascular endothelial growth factor per platelet count in hepatocellular carcinoma, correlations with clinical parameters and survival. J Clin Oncol,2004,34(4):184-190
[57]Giles FJ, Vose JM, Do KA, et al. Clinical relevance of circulating angiogenic factors in patiente with non-Hodgkin's lymphoma or Hodgkin's lymphoma. Leuk Res,2004,28(6):595-604.
[58]Wong mp, Cheung N, Yuen ST, et al. Vascular endothelial growth factor is up-regulated in the early pre-malignant stage of colorectal tumor progression[J]. In J Cancer,1999,81:845-850.
[59]Terris B, Scoazec JY, Rubbia L, etal. Expression of vascular endothelial growth factor in digestive neuroendocrine tumors [J]. Histopathology, 1998,32(2):133-138.
[60]任学琴,景红,傅佩达血管内皮生长因子和微血管密度与结直肠癌侵袭转移的关系。Jounal of Chinese physician.2004,6(5):582-584.
[61]Kimura Y, Sumiyoshi M, Baba K. Antitumor activities of synthetic and natural stilbenes through antiangiogenic action. Cancer Sci,2008,99(10)2083-96.
[62]Kimura Y, Sumiyoshi M, Taniguchi M, et al. Antitumor and antimetastatic actions of anthrone-C-glucoside, cassialoin isolated from Cassia garrettiana heartwood in colon 26-bearing mice. Cancer Sci,2008,99(11):2336-48.
[63]Fernando NT, Koch M, Rothrock C, et al. Tumor escape from endogenous, extracellular matrix-associated angiogenesis inhibitors by up-regulation of multiple proangiogenic factors. Clin Cancer Res,2008,14(5):1529-39.
[64]Xu L, Cochran DM, Tong RT, et al. Placenta growth factor overexpression inhibits tumor growth, angiogenesis, and metastasis by depleting vascular endothelial growth factor homodimers in orthotopic mouse models. Cancer Res, 2006,66(8):3971-3977
[65]Bouquet C, Lamande N, Brand M, et al. Suppression of angiogenesis, tumor growth, and metastasis by adenovirus-mediated gene transfer of human angiotensinogen. Mol Ther,2006,14(2):175-182..
[66]Koskimaki JE, Karagiannis ED, Rosca EV, et al. Peptides derived from type IV collagen, CXC chemokines, and thrombospondin-1 domain-containing proteins inhibit neovascularization and suppress tumor growth in MDA-MB-231 breast cancer xenografts. Neoplasia.2009,11(12):1285-91.
[67]Vidal O, Metges JP, Elizalde I, et al. High preoperative serum vascular endothelial growth factor levels predict poor-clinical outcome after curative resection of gastric cancer. Br J Surg.2009,96(12):1443-51.
[68]Lee SL, Rouhi P, Dahl Jensen L, et al. Hypoxia-induced pathological angiogenesis mediates tumor cell dissemination, invasion, and metastasis in a zebrafish tumor model. Proc Natl Acad Sci U S A.2009,106(46):19485-90.
[69]Shinkai-K,Akedo-H,Mukai-M,et al.Inhibition of in vitro tumor cell invasion by ginsenoside Rg3. Jpn-J-Cancer-Res.1996; 87(4):357-64
[70]Mochizuki-M,Yoo-YC,Matsuzawa-K,et al.Inhibitory effect of tumor metastasis in mice by saponins, ginsenoside-Rb2,20(R)-and 20(S)-ginsenoside-Rg3, of red ginseng. Biol-Pharm-Bull.1995; 18(9):1197-204.
[71]Xu L, Duda DG, di Tomaso E, et al. Direct evidence that bevacizumab, an anti-VEGF antibody, up-regulates SDF1alpha, CXCR4, CXCL6, and neuropilin 1 in tumors from patients with rectal cancer. Cancer Res.2009,69(20):7905-10.
[72]O'Reilly, M.S., Boehm, T., Shing, Y. et al:Endostatin:an endogeneous inhibitor of angiogenesis and tumor growth. Cell 88:277-285,1997
[73]Angiogenesis and its inhibitors. Jpn J Cancer Chemother.1997,24(11): 1585-1593.
[74]Hardwick JC, Van den Brink GR, Offerhaus GJ, et al. NF-kappaB, p38 MAPK and JNK are highly expressed and active in the stroma of human colonic adenomatous polyps. Oncogene.2001,15;20(7):819-27.
[75]Edelblum KL, Goettel JA, Koyama T, et al. TNFR1 promotes tumor necrosis factor-mediated mouse colon epithelial cell survival through RAF activation of NF-kappaB.J Biol Chem.2008,283(43):29485-29494.
[76]Yu HG, Yu LL, Yang Y, et al. Increased expression of RelA/nuclear factor-kappa B protein correlates with colorectal tumorigenesis. Oncology,2003;65(1):37-45.
[77]Higai K, Ishihara S, Matsumoto K. NFkappaB-p65 dependent transcriptional regulation of glycosyltransferases in human colon adenocarcinoma HT-29 by stimulation with tumor necrosis factor alpha. Biol Pharm Bull. 2006,29(12):2372-7.
[78]Chen GG, Lee JF, Wang SH, et al. Apoptosis induced by activation of peroxisome-proliferator activated receptor-gamma is associated with Bcl-2 and NF-kappaB in human colon cancer. Life Sci.2002,70(22):2631-46.
[79]Scaife CL, Kuang J, Wills JC, et al. Nuclear factor kappaB inhibitors induce adhesion-dependent colon cancer apoptosis:implications for metastasis. Cancer Res.2002,62(23):6870-8.
[80]Uetsuka H, Haisa M, Kimura M, et al. Inhibition of inducible NF-kappaB activity reduces chemoresistance to 5-fluorouracil in human stomach cancer cell line. Exp Cell Res,2003,289:27-35
[81]Williams JL, Nath N, Chen J, et al. Growth inhibition of human colon cancer cells by nitric oxide (NO)-donating aspirin is associated with cyclooxygenase-2 induction and beta-catenin/T-cell factor signaling, nuclear factor-kappaB, and NO synthase 2 inhibition:implications for chemoprevention. Cancer Res.2003, 63(22):7613-8.
[82]Fryst H, Oskouian B, Bandhuvula P, et al. Natural sphingadienes inhibit Akt-dependent signaling and prevent intestinal tumorigenesis. Cancer Res. 2009,69(24):9457-9464.
[83]Oraldi M, Trombetta A, biasi F, et al. Decreased polyunsaturated Fatty Acid content contributes to increased survival in human colon cancer. J Oncol.2009, 63(22):7613-8.
[84]Cheung KL, Khor TO, Huang MT,et al. Cancer chemoprevention of azoxymethane/dextran sodium sulfate-induced colon carcinogenesis by phenethyl isothiocyanate and dibenzoylmethane. Carcinogenesis.2009, 14(11):1341-51.
[85]Subauste MC, Ventura-Holman T, Du L,et, al. RACK1 downregulates levels of the pro-apoptotic protein Femlb in apoptosis-resistant colon cancer cells. Cancer Biol Ther.2009,8(23):2297-2305.
[86]Chiou SK, Hoa N. Up-regulation of GADD45alpha expression by NSAIDs leads to apoptotic and necrotic colon cancer cell deaths. Apoptosis. 2009,14(11):1341-51.
[87]Glauben R, Batra A, Stroh T, et al. Histone deacetylases:novel targets for prevention of colitis-associated cancer in mice. Gut.2008,57(5):613-622.
[88]Zhang C, Kolb A, Mattern J, et al. Dexamethasone desensitizes hepatocellular and colorectal tumours toward cytotoxic therapy. Cancer Lett,2006, 242(1):104-111.
[89]Jyoti B, Carlic K, Venkatesh D, et al. Novel retinoic acid metabolism blocking agents endowed with multiple biological activities are efficient growth inhibitors of human breast and prostate cancer cells in vitro and a human breast tumor xenograft in nude mice. J Med Chem,2004,47(27):6716-6729.
[90]Cho SJ, Kim JS, Kim JM, et al. Simvastatin induces apoptosis in human colon cancer cells and in tumor xenografts, and attenuates colitis-associated colon cancer in mice. Int J Cancer.2008,123(4):951-957.
[91]Voboril R, Hochwald SN, Li J, et al. Inhibition of NF-kappa B augments sensitivity to 5-fluorouracil/folinic acid in colon cancer. J Surg Res, 2004,120(2):178-188.
[92]Wood burn JR. The epidermal growth factor receptor and its inhibition in cancer therapy.Pharmacol Ther,1999,82(2-3):241-250.
[93]Boots AW, Hristova M, Kasahara DI, et al. ATP-mediated activation of the NADPH oxidase DUOX1 mediates airway epithelial responses to bacterial stimuli. J Biol Chem.2009,284(26):17858-17867.
[94]Dudek AZ, Lesniewski-Kmak K, Shehadeh NJ, et al. Phase Ⅰ study of bortezomib and cetuximab in patients with solid tumours expressing epidermal growth factor receptor. Br J Cancer.2009,100(9):1379-1384.
[95]Gadgeel SM, Ali S, Philip PA, et al. Genistein enhances the effect of epidermal growth factor receptor tyrosine kinase inhibitors and inhibits nuclear factor kappa B in nonsmall cell lung cancer cell lines. Cancer. 2009,115(10):2165-2176.
[96]Shant J, Cheng K, Marasa BS, et al. Akt-dependent NF-kappaB activation is required for bile acids to rescue colon cancer cells from stress-induced apoptosis. Exp Cell Res.2009,315(3):432-450.
[97]Suh Y, Afaq F, Johnson JJ, et al. A plant flavonoid fisetin induces apoptosis in colon cancer cells by inhibition of COX2 and Wnt/EGFR/NF-kappaB-signaling pathways. Carcinogenesis.2009,30(2):300-307.
[98]Huang L, Verstrepen L, Heyninck K, et al. ABINs inhibit EGF receptor-mediated NF-kappaB activation and growth of EGF receptor-overexpressing tumour cells. Oncogene.2008,27(47):6131-6140.
[99]Ray RM, Bhattacharya S, Johnson LR. EGFR plays a pivotal role in the regulation of polyamine-dependent apoptosis in intestinal epithelial cells. Cell Signal.2007,19(12):2519-2527.
[100]Cascinu S, Berardi R, Salvagni S, et al. A combination of gefitinib and FOLFOX-4 as first-line treatment in advanced colorectal cancer patients. A GISCAD multicentre phase II study including a biological analysis of EGFR overexpression, amplification and NF-kB activation. Br J Cancer. 2008,98(1):71-76.
[101]Iljin K, Karkkanen MJ, Lawrence EC, et al.VEGFR3 gene structure, regulatory region,and sequence polymorphisms [J].FASEB J,2001,15:1028-1036
[102]Hamada T, Ui-Tei K, Miyata Y. A novel gene derived frim developing spinal cords SCDGF, is a unique member of the PDGF/VEGF family [J]. FEBS Lett, 2000,475(2):97-102.
[103]Siemeister G, Marting BG. The alpha-helical domain near the amino terminus is essential for dimerization of vascular endothelial growth factor [J].J Biol Chem,1998,273(18):1115-11120.
[104]Waltenberger J, Claessen EL, Siegbahn A, et al. Different signal transduction properties of KDRand Fltl, two receptors for vascular endothelial grwth factor [J].J Biol Chem,1994,269,(43):2698-2699.
[105]Brown LF,lanir N, McDonagh J, et al. Fbrioblast migration in fibrin gel matrices[J]. Am J Pathol,1993142(1):273-283.
[106]Kubo H, Fujiwara T, L, Invlvement of vascular endothelial growth:factor receptor-3 in maintenance of integrity of endothelial cell lining during tumor angiogenesis[J]. Blood,2004,96(2):546-53.
[107]Gospodarowicz D, Localisation of a fibroblast growth factor and its Effect alone with hydrocortisone on 3T3 cell growth. Nature.1974,249(453):123-129
[108]Zeytin FN, Rusk SF, Baird A, et al. Induction of c-fos, calcitonin gene expression, and acidic fibroblast growth factor production in a multipeptide- secreting neuroendocrine cell line. Endocrinology.1988 Mar; 122(3):1114-1120
[109]Dirix LY, Vermeulen PB, Pawinski A, et al. Elevated levels of the angiogenic cytokines basic fibroblast growth factor and vascular endothelial growth factor in sera of cancer patients. Br J Cancer.1977,76(2):238-243
[110]Davis S, Aldrich TH, Jones PF, et al. Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by Secretion-Trap expression cloing. Cell,1996,87(7):1161-1170
[111]Maisonpierre PC, Suri C, Jones PF, et al. Angiopoietin-2, a natural antiagonist for tie2 that disrupt in vivo angiogenesis. Science,1997,277(5322):55-60
[112]Valenzuela DM, Griffiths JA, Rojas J, et al. Angiopoietins 3 and 4:Diverging gene counterparts in mice and humans. Proc Natl Acad Sci USA,1999, 96(5):1904-1909
[113]Lee JH, Koh JT, Shin BA, et al. Comparative study of angiostatic and anti-invasive gene expressions as prognostic factors in gastric cancer[J]. Oncol, 2001,18(2):355-61
[114]Syed A Ahmad, Wenbiao Liu, Yong D Jung, etal. The effects of angiopoietin-1 and 2 on tumor growth ang angiogenesis in human colon cancer. Cancer Res, 2001,61:1255-1259
[115]Anne Saaristo, Terhi Karpanen, Kari Alitalo. Mechanisms of angiogenesis and their use in the inhibitions of tumor growth and metastasis. Oncogene, 2000,19:6122-6129
[116]Ahmad SA, Liu W, Jung YD, et al. Differential expression of angiopoietin-1and angiopoietin-2 in colon carcinoma. Cancer,2001,92(5):1138-1143
[117]Etoh T, Inoue H, Tanaka S, et al. Angiopoietin-2 is related to tumor angiogenesis in gastric carcinoma:possible in vivo regulation via induction of proteases. Cancer Res,2110,61(5):2145-2153
[118]Tanaka S, Sugimachi K, Yamashita Yi Y, et al. Tie2 vascular endothelial receptor expression and function in hepatocellular carcinoma. Hepathology, 2002,35(4):861-867
[119]Furukawa T, Yoshimura A, Sumizawa T, et al. Angiogenic factor. Nature,356:668
[120]Stevenson DP, Milligan SR, Collins WP, et al. Effects of platelet-derived endothelial cell growth factor/thymidine phosphorlase, substrate, and products in three-dimensional model of angiogenesis. AJP,1998,152:1641-1646
[121]Pujimoto K, Hosotaoi R, Wada M, et al. Expression of two angiogenic factors, vascular endothelial growth factor and platelet derived endothelial growth factor in human pancreafic cancer, and its relationship to angiogenesis. Eur J Cancer, 1998,34(9):1439-1447
[122]Takao S, Takebeyashi Y, Che X, et al. Expression of thymidine phosphorylase is associated with a poor progrosis in patients with ductal adenocarcinoma of the pancreas. Clin Cancer Res,1998,4(7):1619-1624
[123]Zelinski DP, Zantek ND, Stewart J C, et al. EphA2 over-expression causes tumorgenesis of mammary epithelial cells[J]. Cancer,2001,61(9):2301-2306.
[124]Liu W, Ahmad SA, Jung YD, et al. Coexpression of EphrinBs and receptors in colon carcinoma[J]. Cancer,2002,94(4):934-939.
[125]Brantley DM, Chen N, Thompson EJ, et al. Soluble EphA receptors inhibit tumor angiogenesis and progression in vivo[J]. Oncogene,2002,21(46): 7011-7026.
[126]Zhong H, De-Marzo AM, Laughner E, et al. Overexpression of hypoxia-inducible-factor-1 alpha in common human cancers and their metastasis. Cancer Res,1999,59:5830-5835.
[127]Sivridis E, Giatromanolaki A, Gatter KC, et al. Association of hypoxia-inducible-factor-1 alpha and 2alpha with activated angiogenic pathways and prognosis in pations with endometrial carcinoma. Cancer, 2002,95(5):1055-1064
[128]Carmeliet P, Dor Y, Hewbert JM, et al. Role of HIF-1 alpha in hypoxia-nediated apoptosis, cell proliferation ang tumor angiogenesis. Nature,1998,394:485-490.
[129]O'reilly MS, Holmgren L, Shin Y, et al. Angiostatin:a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell.1994;79:315-328.
[130]Stathakis P, Fitzgerald M,Lisa J, et al. Generation of Angiostatin by reduction and proteolysis of Plasmin [J].J biolog chemi,1997,272(33):20641-20645.
[131]Welsh CL, Welsh, Ito B, et al. Angiostatin induces endothelial cell apoptosis and activation of focal adhesion kinase independently of the integrin-binding motif RGD. Proc Natl Acad Sci U.S.A.1998;95:5579-5583.
[132]Yihai Cao, Richard WJi, Dong Davidson, et al. Kringle domains of Human Angiostatin [J]. The Journal of biological chemistry,1996,271(46):29461-29467.
[133]Yihai Cao, Andrew Chen, Seong Soo A, et al. Kringle 5 of Plasminogen is a Novel Inhibitor of Endothelial Cell Growth [J].The journal of biological chemistry,1997,272(36):22924-22928.
[134]Hanaha D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis [J]. Cell,1996,86:353-364.
[135]Yihai Cao, Michael S, O'Reilly, et al. Expression of angiostatin cDNA in a Murine fibrosarcoma suppresses primary tumor growth and produces long-term dormancy of metastases [J]. J Clin Invest,1998,101(5):1055-1063.
[136]Gupta N, Nodzenski E, Khodarev NN, et al. Angiostatin effects on endothelial cells mediated by ceramide and RhoA. EMBO,2001,2(6):536-540
[137]Moser TL, Kenan DJ, Ashley TA, et al. Endothelial cell surface F1-F0 ATP synthase is active in ATP synthesis and is inhibited by angiostatin. Proc Natl Acad Sci USA,2001,98(12):6656-6661.
[138]Jiang L, Jha V, Dhanabal M, et al. Intracellular Ca(2) signaling in endothelial cells by the angiogenesis inhibitors endostatin and angiostatin. Am J Physiol Cell Physiol,2001,280(5):1140-1150
[139]Rony S, Edwin GK. The MAPK signaling cascade. FASEB,1995,9:726-735.
[140]O'Reilly MS, Boehm T, Shing Y, et al. Endostatin:an endogenous inhibitor of angiogenesis and tumor growth. Cell,1997,88(2):277-85
[141]Blezinger P, Wang J, Gondo m, et al. Systemic inhibitor of tumor growth and tumor metastasis by intramuscular administration of the enstatin gene. Nat Bio Technol,1999,17(4):343-349.
[142]Youngmi K, Jinwook J, Ok Hee J, et al. Endostatin inhibits endothelial and tumorcellular invasion by blocking the activation and catalytic of matrix metalloproteinase 2. Cancer Res,2000,60:5410-5413.
[143]MOhanraj D, Ramami R, Ruediger V, et al. Endostatin:Yeast production, mutant, and antitumor effect in renal cell carcinoma. Cancer Res, 1999,39:189-197.
[144]Yokoyama Y, Dhamabal M, Griffioen Aw, et al. Synergy between angiostatin and endostatin:inhibition of overian cancer growth. Cancer Res,2000,60: 2190-2196
[145]Perletti A, concari P, Giardini R, et al. Antitumor activity of endostatin against carcinogen-induced rat primary mammary tumor. Cancer Res,2000,61: 1793-1796.
[146]Kirsh M, Schackert G, Black PM. Anti-angiogenic treatment strategies for malignant brain tumor. J Neurooncol,2000,50:149-163.
[147]Mohanraj Dhanabal, Ramani Ramchandran,et al. Endostatin Induces Endothelial Cell Apoptosis.J Biol Chem,1999,274(17):11721-11726.
[148]Johan Dixelius, Helena Larsson Endostatin-induced tyrosine kinase signaling through the Shb adaptor protein regulates endothelial cell apoptosis.Blood, 2000,95(11):3403-3411.
[149]Rehn M, Veikkola T, Kukk Valdre E, et al.Interaction of endostatinwith integrins implicated in angiogenesis.Proc Natl Acad Sci USA,2001,98 (3):1024-1029.
[150]Shichiri M, Hirata Y.Antiangiogenesisignals by endostatin.FASEB J,2001,15 (6):1044-1053.
[151]Donald R. Senger, Kevin P. Claffey, et al. Angiogenesis promoted by vascular endothelial growth factor:Regulation through 11 and 21 integrins. Proc. Natl. Acad. Sci. USA.1997,94(25):13612-13617.
[152]Hayyes AJ, Li LY, Lippman ME. Antivascular therapy:a new approach to cancer treatment. BMJ,1999,318(7187):853-855
[153]Jimyenez B, Volpert OV, Crawford SE, et al. Signals leading to apoptosis-dependent inhibition of neovascularization by thrombospondin. Nat Med,2000,6(1):41-48.
[154]Bleuel K, Popp S, Fusenig NE, et al. Tumor suppression in human skin carcinoma cells by chromosome 15 transfer or thrombospondin-1 overexpression through halted tumor vascularization. Proc Natl Acad Sci USA, 1999,96(5):2065-2070.
[155]Narazaki M, Tosato G. Canstatin:an inhibitor of angiogenesis and tumor growth revisited. Cancer J 2006; 12:110-112
[156]Kamphaus GD, Colorado PC, Panka DJ, Hopfer H, Ramchandran R, Torre A, Maeshima Y, Mier JW, Sukhatme VP, Kalluri R. Canstatin, a novel matrix-derived inhibitor of angiogenesis and tumor growth. J Biol Chem 2000; 275:1209-1215
[157]Kamphaus GD, Colorado PC, Panka DJ, et al. Canstatin, a novel matrix-derived inhibitor of angiogenesis and tumor growth. J Biol Chem, 2000,275(2):1209-1215
[158]Sen R, Baltimore D. Inducibility of the immunoglobulin enhancer-binding protein NF-KB by a posttranslational mechaniam. Cell,1986,47:921-928
[159]Baeuerle PA,Henkel T. Function and activation of NF-kappa B in the immune system[J]. Annu Rev Immunol,1994,12:141-179
[160]Baeuerle PA, Baltimore D. NF-kappa B:ten years after. Cell.199687(1):13-20.
[161]Christman JW, Sadikot RT, Blackwell TS. The role of nuclear factor-kappa B in pulmonary diseases. Chest.2000,117(5):1482-7.
[162]Beg AA, Sha WC, Bronson RT,et al. Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-kappa B. [J]. Nature, 1995,376 (6536)::167-170.
[163]Iimuro Y,Nishiura T,Hellerbrand C,et al. NFkappaB prevents apoptosis and liver dysfunction during liver regeneration. [J]. J Clin Invest,1998,101: 802-811.
[164]Wang CY, Mayo MW, Baldwin AS. TNF-and cancer therapy-induced apoptosis: potentiation by inhibition of NF-kappaB. [J]. Science,1996,274:784-787.
[165]Wang CY,Guttridge DC,Mayo MW,et al. NF-kappa B induces expression of the Bcl22 homologue Al/Bfl-1 to preferentially suppresschemotherapy-induced apoptosis[J].Mol Cell Biol,1999,19:5923-59291
[166]Lee HH,Dadgostar H,Cheng Q,et al. NF-kappa B-mediated up-regulation of Bcl-x and Bfl/Al is required for CD40 survival signaling in B lymphocytes[J]. Proc Natl Acad Sci USA,1999,96:9136-91411
[167]Wang CY,Mayo MW,Korneluk RG,et al. NF-kappa B antiapoptosis:induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 tosuppress caspase-8 activation [J]. Science,1999,281:1680-16831
[168]Wu MX,Ao Z,Prasad KV,et al. IEX-1L,an apoptosis inhibitor involved in NF-kappa B-mediated cell survival [J]. Science,1999,281:998-10011
[169]Bushdid PB, Brantley DM, Yull FE, et al. Inhibition of NF-kappaB activity results in disruption of the apical ectodermal ridge and aberrant limb morphogenesis. Nature,1998,9;392(6676):615-8.
[170]Hardwick JC, Van den Brink GR, Offerhaus GJ, et al. NF-kappaB, p38 MAPK and JNK are highly expressed and active in the stroma of human colonic adenomatous polyps. Oncogene.2001,15;20(7):819-27.
[171]Yu HG, Yu LL, Yang Y, et al. Increased expression of RelA/nuclear factor-kappa B protein correlates with colorectal tumorigenesis. Oncology,2003;65(1):37-45.
[172]Lee DK, Park SY, Baik SK, et al. Deoxycholic acid-induced signal transduction in HT-29 cells:role of NF-kappa B and interleukin-8. Korean J Gastroenterol. 2004,43(3):176-85.
[173]Chen GG, Lee JF, Wang SH, et al. Apoptosis induced by activation of peroxisome-proliferator activated receptor-gamma is associated with Bcl-2 and NF-kappaB in human colon cancer. Life Sci.2002,70(22):2631-46.
[174]Scaife CL, Kuang J, Wills JC, et al. Nuclear factor kappaB inhibitors induce adhesion-dependent colon cancer apoptosis:implications for metastasis. Cancer Res.2002,62(23):6870-8.
[175]Uetsuka H, Haisa M, Kimura M, et al. Inhibition of inducible NF-kappaB activity reduces chemoresistance to 5-fluorouracil in human stomach cancer cell line. Exp Cell
[176]Williams JL, Nath N, Chen J, et al. Growth inhibition of human colon cancer cells by nitric oxide (NO)-donating aspirin is associated with cyclooxygenase-2 induction and beta-catenin/T-cell factor signaling, nuclear factor-kappaB, and NO synthase 2 inhibition:implications for chemoprevention. Cancer Res.2003, 63(22):7613-8
[177]Rakitina TV, Vasilevskaya IA, O'Dwyer PJ. Additive interaction of oxaliplatin and 17-allylamino-17-demethoxygeldanamycin in colon cancer cell lines results from inhibition of nuclear factor kappaB signaling. Cancer Res.2003, 15;63(24):8600-5.
[178]Din FV, Dunlop MG, Stark LA. Evidence for colorectal cancer cell specificity of aspirin effects on NF kappa B signalling and apoptosis. Br J Cancer.2004, 91(2):381-8.
[179]Higai K, Ishihara S, Matsumoto K. NFkappaB-p65 dependent transcriptional regulation of glycosyltransferases in human colon adenocarcinoma HT-29 by stimulation with tumor necrosis factor alpha. Biol Pharm Bull. 2006,29(12):2372-7.
[180]Thorns HC, Dunlop MG, Stark la. p38-mediated inactivation of cyclin Dl/cyclin-dependent kinase 4 stimulates nucleolar translocation of RelA and apoptosis in colorectal cancer cells. Cancer Res.2007,67(4):1660-9
[181]Yu HG, Yu LL, Yang Y, et al. Increased expression of RelA/nuclear factor-kappa B protein correlates with colorectal tumorigenesis. Oncology,2003;65(1):37-45.
[182]Lee DK, Park SY, Baik SK, et al. Deoxycholic acid-induced signal transduction in HT-29 cells:role of NF-kappa B and interleukin-8. Korean J Gastroenterol. 2004,43(3):176-85.
[183]Chen GG, Lee JF, Wang SH, et al. Apoptosis induced by activation of peroxisome-proliferator activated receptor-gamma is associated with Bcl-2 and NF-kappaB in human colon cancer. Life Sci.2002,70(22):2631-46.
[184]Scaife CL, Kuang J, Wills JC, et al. Nuclear factor kappaB inhibitors induce adhesion-dependent colon cancer apoptosis:implications for metastasis. Cancer Res.2002,62(23):6870-8.
[185]Uetsuka H, Haisa M, Kimura M, et al. Inhibition of inducible NF-kappaB activity reduces chemoresistance to 5-fluorouracil in human stomach cancer cell line. Exp Cell
[186]Williams JL, Nath N, Chen J, et al. Growth inhibition of human colon cancer cells by nitric oxide (NO)-donating aspirin is associated with cyclooxygenase-2 induction and beta-catenin/T-cell factor signaling, nuclear factor-kappaB, and NO synthase 2 inhibition:implications for chemoprevention. Cancer Res.2003, 63(22):7613-8
[187]Rakitina TV, Vasilevskaya IA, O'Dwyer PJ. Additive interaction of oxaliplatin and 17-allylamino-17-demethoxygeldanamycin in colon cancer cell lines results from inhibition of nuclear factor kappaB signaling. Cancer Res.2003, 15;63(24):8600-5.
[188]Voboril R, Hochwald SN, Li J, et al. Inhibition of NF-kappa B augments sensitivity to 5-fluorouracil/folinic acid in colon cancer. J Surg Res, 2004,120(2):178-188.
[189]Din FV, Dunlop MG, Stark LA. Evidence for colorectal cancer cell specificity of aspirin effects on NF kappa B signalling and apoptosis. Br J Cancer.2004, 91(2):381-8.
[190]Higai K, Ishihara S, Matsumoto K. NFkappaB-p65 dependent transcriptional regulation of glycosyltransferases in human colon adenocarcinoma HT-29 by stimulation with tumor necrosis factor alpha. Biol Pharm Bull. 2006,29(12):2372-7.