HAb18G/CD147调控肝癌细胞自噬的研究
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摘要
肿瘤是严重威胁人类健康的主要疾病之一。恶性肿瘤在生长过程中,由于增生过快造成局部组织严重缺氧和营养匮乏,肿瘤细胞通过调整代谢反应、改变DNA修复机制、诱导血管生成等机制适应这种恶劣的环境变化。因此,探讨肿瘤细胞对缺氧和饥饿的适应机制对有效地控制肿瘤的进展具有十分重要的意义。
自噬性细胞死亡(autophagic cell death)是近年来发现的一种新型的程序性细胞死亡方式。当细胞处于不良环境(如饥饿)时,通过适度的自噬作用降解自身物质以满足细胞生存的基本物质和能量需求,求得生存;但过度的自噬将导致细胞发生自噬性死亡。近年来的研究证实,肿瘤在无血管生成的前期,乏氧/养的肿瘤环境诱导肿瘤细胞发生自噬。自噬是调节肿瘤细胞适应环境的一种新的机制。
HAb18G/CD147是在多种恶性肿瘤细胞高表达的黏附分子,是基质金属蛋白酶(Matrix metalloproteinase, MMPs)的诱导因子,促进肿瘤的侵袭和转移。目前越来越多的研究表明,HAb18G/CD147还参与了多种细胞信号通路调节,调控肿瘤细胞的能量代谢和物质代谢。HAb18G/CD147被认为是肿瘤发展进程中一个重要的分子。那么HAb18G/CD147是否参与调控肝癌细胞的自噬和自噬性细胞死亡?这是本课题要回答的关键问题。
本实验分为三部分:
第一部分:饥饿状态下HAb18G/CD147分子在肝癌细胞中的表达变化
选取三种肝癌细胞(SMMC7721、HepG2、HCC9204),采用氨基酸饥饿模拟肿瘤细胞的营养缺乏,通过Western Blot分别检测三种细胞在饥饿不同时间后HAb18G/CD147分子的表达变化。结果表明,氨基酸饥饿1,3,6,12 h后三种肝癌细胞的HAb18G/CD147的表达均迅速上调,饥饿24 h后其表达量均有所下降。其中SMMC7721细胞在饥饿1-12 h内HAb18G/CD147的表达相对维持在一个较高的稳定水平。
第二部分:HAb18G/CD147参与肝癌细胞SMMC7721自噬调控的研究
在第一部分实验的基础上,选用SMMC7721肝癌细胞作为研究HAb18G/CD147调控饥饿诱导自噬的细胞模型。采用12 h全氨基酸缺乏诱导自噬。我们通过RNA干涉的方法降低了HAb18G/CD147的表达,利用免疫荧光技术和透射电子显微镜(TEM)技术检测自噬。采用台盼蓝排斥实验检测细胞死亡,并利用自噬的特异性抑制剂3-甲基嘌呤(3-MA)抑制自噬,从而观察HAb18G/CD147是否可以下调饥饿诱导的自噬性细胞死亡。结果显示,与无关干涉相比,在转染si-HAb18G的SMMC7721细胞中,经过12 h饥饿后,其HAb18G/CD147无论在RNA水平还是蛋白水平的表达均显著降低;同时,在饥饿12 h后,转染了si-HAb18G干涉片段的SMMC7721细胞的自噬水平明显高于对照组,并且HAb18G/CD147抑制饥饿诱导的自噬存在剂量依赖效应,说明HAb18G/CD147在SMMC7721细胞中可以显著抑制饥饿诱导的自噬;干涉HAb18G后,细胞死亡数量明显增加,加入自噬的抑制剂3-甲基嘌呤(3-MA)可以明显降低细胞的死亡率,说明HAb18G可以抑制饥饿诱导的自噬性细胞死亡。
第三部分:HAb18G/CD147参与肝癌细胞SMMC7721自噬调控的信号通路
为了探讨HAb18G/CD147如何调控细胞自噬,我们检测了自噬相关基因ATG5、ATG6/Beclin 1和ATG8/LC3的表达变化。结果发现,在HAb18G干涉组和对照组,ATG5和ATG8的表达水平无显著差异;但在siRNA-HAb18G干涉模型组,ATG6/Beclin 1的表达明显高于无关干涉组。ATG6/Beclin 1是调控自噬的关键蛋白之一,它不仅促进自噬泡(autophagosome)形成,同时与Class III PI3K形成复合物,促进自噬泡(autophagosome)与溶酶体(lysome)融合。我们的进一步研究发现HAb18G/CD147可以抑制ATG6/Beclin 1在蛋白水平的表达,进而抑制饥饿诱导的自噬,从而避免肿瘤细胞因过度自噬导致细胞死亡。同时,我们的研究也发现HAb18G/CD147抑制ATG6/Beclin 1的表达可能涉及到Class I PI3K信号通路。提示HAb18G/CD147抑制肿瘤细胞的过度自噬可能是通过Class I PI3K通路调节ATG6/Beclin 1表达,从而抑制自噬。
Cancer is common diseases and has a serious hazard to human health, which not only endangers the lives of patients, but brings enormous social impact of the medical world. Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and ranks sixth among cancers as cause of death worldwide and third in China. It has an annual incidence rate of 564000 cases, and 55% of those are in China.
High invasion and metastasis abilities of HCC are the important reasons to the high mortality. In the process of tumor metastasis, matrix metalloproteinases (MMPs) play an important role in the degradation extracelluar matrix. HAb18G/CD147 is inducer of MMPs, which plays key functions in cancer metastasis. HAb18G/CD147, a plasmolemma glucoprotein, takes part in many physiological and pathological processes and plays a majar role in many functions, including tumor invasion and metastasis, inflammation, cell adhesion and embryonic development.
Our lab prepared monoclonal antibody HAb18 in 1987, which is specific to HCC. We obtained a HCC associated antigen, HAb18G using HAb18 as the probe to screen the HCC cDNA library. The ORF (open reading frame) sequence of HAb18G is homologous to that of CD147 molecule. HAb18G has generally been acknowledged as a new member of CD147 superfamily. Our previous studies showed that HAb18G was highly expressed in HCC tissues and lowly expressed in nomal tissues. We have discovered that the function of HAb18G is similar to CD147/EMMPRIN (Extracellar matrix metalloproteinase inducer) and this molecule could induce HCC cells and fibroblast cells to secret MMPs and promote tumor invasion.
One of most important functions of HAb18G/CD147 is to induce the production of MMPs. However, whether there are other mechanisms explaining the role of HAb18G/CD147 in tumor progression remains to be elucidated. In this study, we investigated the functional effects of HAb18G/CD147 expression on autophagy in hepatoma cell line SMMC 7721 using immunostainning, Western Blot and transmission electronmicroscopy. We found that HAb18G/CD147 could inhibit starvation-induced autophagy in SMMC 7721 cells. The result of RNA interference experiment for HAb18G/CD147 indicated that autophagy significantly increased in SMMC 7721 cells, compared with scramble control. Meanwhile, cell death ratio increased in SMMC7721 cells transfected with HAb18G siRNA. In addition, we found that HAb18G/CD147 inhibited starvation-induced autophagy via down-regulating Beclin1 expression, which led to decrease the formation of autophagosome. Furthermore, HAb18G/CD147 inhibiting ATG6/Beclin 1 expression via the Class I PI3K/AKT pathway, which is confirmed by class I PI3K inhibitor LY294002. Our findings indicate that HAb18G/CD147 can protect cancer cells by inhibiting excessive autophagy to avoid autophagic death pathway in starvation condition. These results may lead to a better understanding of regulation mechanism of human SMMC7721 liver cancer cells in starvation condition.
Part 1: HAb18G/CD147 expression in hepatoma cells under starvation condition
To detect HAb18G/CD147 expression in hepatoma cells under starvation condiction, we selected three hepatoma cell lines (SMMC7721, HepG2 and HCC9204), which were synchronized by starvation in amino acids free EBSS buffer for 0, 1, 3, 6, 12, 24 hours at 37°C. HAb18G/CD147 expression was detected by using Western Blot. These results showed that HAb18G/CD147 expression was significantly increased when the hepatoma cells were starvated for 1, 3, 6, 12 h.
Part 2: HAb18G/CD147 inhibits starvation-induced autophagy in human hepatoma cell SMMC7721.
In this part, we investigated the functional effects of HAb18G/CD147 on autophagy in hepatoma cell line SMMC7721 using immunofluoscence staining, Western Blot and transmission electronmicroscopy. Our data showed that HAb18G small interference RNA considerably down-regulated the expression of HAb18G/CD147 in SMMC7721 cells at both mRNA and protein levels. The down-regulation of HAb18G/CD147 significantly promoted the starvation-induced autophagy in a dose-dependent manner. Using trypan blue exclusion assay, we found that HAb18G/CD147 notably enhanced the survival of SMMC7721 cells through inhibiting starvation-induced autophagy.
Part 3: Signaling pathway of starvation-induced autophagy inhibition by HAb18G/CD147
In this part, we first assayed the epression of autophagy-relative genes including ATG5, ATG6/Beclin 1, and ATG8/LC3 using RT-PCR. We demonstrated that HAb18G/CD147 down-regulated the expression of autophagy-regulating gene ATG6/Beclin 1 in SMMC7721 cells. Then, our result showed that HAb18G/CD147 down-regulated the expression of ATG6/Beclin 1 protein in SMMC7721 cells. Furthermore, our data indicated that HAb18G siRNA-transfected SMMC7721 cells had a significantly decreased level of phosphorylated serine-threonine kinase Akt (pAkt) and the expression of Beclin 1 was inversely associated with the level of pAkt, suggesting that the Class I phosphatidylinositol 3-kinase-Akt pathway might be involved in the down-regulation of ATG6/Beclin 1.
自噬性细胞死亡(autophagic cell death)是近年来发现的一种新型的程序性细胞死亡方式。当细胞处于不良环境(如饥饿)时,通过适度的自噬作用降解自身物质以满足细胞生存的基本物质和能量需求,求得生存;但过度的自噬将导致细胞发生自噬性死亡。近年来的研究证实,肿瘤在无血管生成的前期,乏氧/养的肿瘤环境诱导肿瘤细胞发生自噬。自噬是调节肿瘤细胞适应环境的一种新的机制。
HAb18G/CD147是在多种恶性肿瘤细胞高表达的黏附分子,是基质金属蛋白酶(Matrix metalloproteinase, MMPs)的诱导因子,促进肿瘤的侵袭和转移。目前越来越多的研究表明,HAb18G/CD147还参与了多种细胞信号通路调节,调控肿瘤细胞的能量代谢和物质代谢。HAb18G/CD147被认为是肿瘤发展进程中一个重要的分子。那么HAb18G/CD147是否参与调控肝癌细胞的自噬和自噬性细胞死亡?这是本课题要回答的关键问题。
本实验分为三部分:
第一部分:饥饿状态下HAb18G/CD147分子在肝癌细胞中的表达变化
选取三种肝癌细胞(SMMC7721、HepG2、HCC9204),采用氨基酸饥饿模拟肿瘤细胞的营养缺乏,通过Western Blot分别检测三种细胞在饥饿不同时间后HAb18G/CD147分子的表达变化。结果表明,氨基酸饥饿1,3,6,12 h后三种肝癌细胞的HAb18G/CD147的表达均迅速上调,饥饿24 h后其表达量均有所下降。其中SMMC7721细胞在饥饿1-12 h内HAb18G/CD147的表达相对维持在一个较高的稳定水平。
第二部分:HAb18G/CD147参与肝癌细胞SMMC7721自噬调控的研究
在第一部分实验的基础上,选用SMMC7721肝癌细胞作为研究HAb18G/CD147调控饥饿诱导自噬的细胞模型。采用12 h全氨基酸缺乏诱导自噬。我们通过RNA干涉的方法降低了HAb18G/CD147的表达,利用免疫荧光技术和透射电子显微镜(TEM)技术检测自噬。采用台盼蓝排斥实验检测细胞死亡,并利用自噬的特异性抑制剂3-甲基嘌呤(3-MA)抑制自噬,从而观察HAb18G/CD147是否可以下调饥饿诱导的自噬性细胞死亡。结果显示,与无关干涉相比,在转染si-HAb18G的SMMC7721细胞中,经过12 h饥饿后,其HAb18G/CD147无论在RNA水平还是蛋白水平的表达均显著降低;同时,在饥饿12 h后,转染了si-HAb18G干涉片段的SMMC7721细胞的自噬水平明显高于对照组,并且HAb18G/CD147抑制饥饿诱导的自噬存在剂量依赖效应,说明HAb18G/CD147在SMMC7721细胞中可以显著抑制饥饿诱导的自噬;干涉HAb18G后,细胞死亡数量明显增加,加入自噬的抑制剂3-甲基嘌呤(3-MA)可以明显降低细胞的死亡率,说明HAb18G可以抑制饥饿诱导的自噬性细胞死亡。
第三部分:HAb18G/CD147参与肝癌细胞SMMC7721自噬调控的信号通路
为了探讨HAb18G/CD147如何调控细胞自噬,我们检测了自噬相关基因ATG5、ATG6/Beclin 1和ATG8/LC3的表达变化。结果发现,在HAb18G干涉组和对照组,ATG5和ATG8的表达水平无显著差异;但在siRNA-HAb18G干涉模型组,ATG6/Beclin 1的表达明显高于无关干涉组。ATG6/Beclin 1是调控自噬的关键蛋白之一,它不仅促进自噬泡(autophagosome)形成,同时与Class III PI3K形成复合物,促进自噬泡(autophagosome)与溶酶体(lysome)融合。我们的进一步研究发现HAb18G/CD147可以抑制ATG6/Beclin 1在蛋白水平的表达,进而抑制饥饿诱导的自噬,从而避免肿瘤细胞因过度自噬导致细胞死亡。同时,我们的研究也发现HAb18G/CD147抑制ATG6/Beclin 1的表达可能涉及到Class I PI3K信号通路。提示HAb18G/CD147抑制肿瘤细胞的过度自噬可能是通过Class I PI3K通路调节ATG6/Beclin 1表达,从而抑制自噬。
Cancer is common diseases and has a serious hazard to human health, which not only endangers the lives of patients, but brings enormous social impact of the medical world. Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and ranks sixth among cancers as cause of death worldwide and third in China. It has an annual incidence rate of 564000 cases, and 55% of those are in China.
High invasion and metastasis abilities of HCC are the important reasons to the high mortality. In the process of tumor metastasis, matrix metalloproteinases (MMPs) play an important role in the degradation extracelluar matrix. HAb18G/CD147 is inducer of MMPs, which plays key functions in cancer metastasis. HAb18G/CD147, a plasmolemma glucoprotein, takes part in many physiological and pathological processes and plays a majar role in many functions, including tumor invasion and metastasis, inflammation, cell adhesion and embryonic development.
Our lab prepared monoclonal antibody HAb18 in 1987, which is specific to HCC. We obtained a HCC associated antigen, HAb18G using HAb18 as the probe to screen the HCC cDNA library. The ORF (open reading frame) sequence of HAb18G is homologous to that of CD147 molecule. HAb18G has generally been acknowledged as a new member of CD147 superfamily. Our previous studies showed that HAb18G was highly expressed in HCC tissues and lowly expressed in nomal tissues. We have discovered that the function of HAb18G is similar to CD147/EMMPRIN (Extracellar matrix metalloproteinase inducer) and this molecule could induce HCC cells and fibroblast cells to secret MMPs and promote tumor invasion.
One of most important functions of HAb18G/CD147 is to induce the production of MMPs. However, whether there are other mechanisms explaining the role of HAb18G/CD147 in tumor progression remains to be elucidated. In this study, we investigated the functional effects of HAb18G/CD147 expression on autophagy in hepatoma cell line SMMC 7721 using immunostainning, Western Blot and transmission electronmicroscopy. We found that HAb18G/CD147 could inhibit starvation-induced autophagy in SMMC 7721 cells. The result of RNA interference experiment for HAb18G/CD147 indicated that autophagy significantly increased in SMMC 7721 cells, compared with scramble control. Meanwhile, cell death ratio increased in SMMC7721 cells transfected with HAb18G siRNA. In addition, we found that HAb18G/CD147 inhibited starvation-induced autophagy via down-regulating Beclin1 expression, which led to decrease the formation of autophagosome. Furthermore, HAb18G/CD147 inhibiting ATG6/Beclin 1 expression via the Class I PI3K/AKT pathway, which is confirmed by class I PI3K inhibitor LY294002. Our findings indicate that HAb18G/CD147 can protect cancer cells by inhibiting excessive autophagy to avoid autophagic death pathway in starvation condition. These results may lead to a better understanding of regulation mechanism of human SMMC7721 liver cancer cells in starvation condition.
Part 1: HAb18G/CD147 expression in hepatoma cells under starvation condition
To detect HAb18G/CD147 expression in hepatoma cells under starvation condiction, we selected three hepatoma cell lines (SMMC7721, HepG2 and HCC9204), which were synchronized by starvation in amino acids free EBSS buffer for 0, 1, 3, 6, 12, 24 hours at 37°C. HAb18G/CD147 expression was detected by using Western Blot. These results showed that HAb18G/CD147 expression was significantly increased when the hepatoma cells were starvated for 1, 3, 6, 12 h.
Part 2: HAb18G/CD147 inhibits starvation-induced autophagy in human hepatoma cell SMMC7721.
In this part, we investigated the functional effects of HAb18G/CD147 on autophagy in hepatoma cell line SMMC7721 using immunofluoscence staining, Western Blot and transmission electronmicroscopy. Our data showed that HAb18G small interference RNA considerably down-regulated the expression of HAb18G/CD147 in SMMC7721 cells at both mRNA and protein levels. The down-regulation of HAb18G/CD147 significantly promoted the starvation-induced autophagy in a dose-dependent manner. Using trypan blue exclusion assay, we found that HAb18G/CD147 notably enhanced the survival of SMMC7721 cells through inhibiting starvation-induced autophagy.
Part 3: Signaling pathway of starvation-induced autophagy inhibition by HAb18G/CD147
In this part, we first assayed the epression of autophagy-relative genes including ATG5, ATG6/Beclin 1, and ATG8/LC3 using RT-PCR. We demonstrated that HAb18G/CD147 down-regulated the expression of autophagy-regulating gene ATG6/Beclin 1 in SMMC7721 cells. Then, our result showed that HAb18G/CD147 down-regulated the expression of ATG6/Beclin 1 protein in SMMC7721 cells. Furthermore, our data indicated that HAb18G siRNA-transfected SMMC7721 cells had a significantly decreased level of phosphorylated serine-threonine kinase Akt (pAkt) and the expression of Beclin 1 was inversely associated with the level of pAkt, suggesting that the Class I phosphatidylinositol 3-kinase-Akt pathway might be involved in the down-regulation of ATG6/Beclin 1.
引文
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