MicroRNA-100 promotes the autophagy of hepatocellular carcinoma cells by inhibiting the expression of mTOR and IGF-1R.
MicroRNA-100 promotes the autophagy of hepatocellular carcinoma cells by inhibiting the expression of mTOR and IGF-1R.
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MicroRNA-100通过抑制mTOR和IGF-1R表达促进肝癌细胞自噬
DOI：
10.18632/oncotarget.2189
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发表时间：
2014-08-15
期刊：
影响因子：
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通讯作者：
Zhuang SM
中科院分区：
文献类型：
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作者：
Ge YY;Shi Q;Zheng ZY;Gong J;Zeng C;Yang J;Zhuang SM
我们发现，恢复miR-100的表达导致肝细胞癌（HCC）细胞中LC3B-II的积累和p62的降低，而miR-100的拮抗作用降低了LC3B-II的水平。此外，在人HCC组织中观察到miR-100下调与p62上调之间存在显著相关性，表明miR-100具有促进自噬的作用。随后的研究表明，Atg7的敲低而Beclin-1的敲低可减弱mir -100诱导的LC3B-II升高。此外，miR-100过表达导致大量细胞死亡，而Atg7沉默和氯喹处理可以消除这种现象。同时，miR-100的表达导致Annexin v染色细胞比例增加，线粒体电位丧失，这意味着miR-100可能促进atg7依赖性自噬和随后的凋亡细胞死亡。同样，小鼠异种移植模型显示miR-100抑制HCC细胞的体内生长。我们进一步发现miR-100通过结合mTOR和IGF-1R的3 '非翻译区抑制mTOR和IGF-1R的表达，敲低mTOR或IGF-1R可表型化miR-100的促自噬作用，表明miR-100可能通过降低mTOR和IGF-1R水平促进自噬。总之，我们的数据揭示了自噬的新调控机制和miR-100的新功能，并为HCC提供了潜在的治疗靶点。
We found that restoration of miR-100 expression resulted in accumulation of LC3B-II and decrease of p62 in hepatocellular carcinoma (HCC) cells, whereas antagonism of miR-100 reduced the level of LC3B-II. Moreover, a significant correlation between miR-100 downregulation and p62 upregulation was observed in human HCC tissues, suggesting an autophagy-promoting effect of miR-100. Subsequent investigations disclosed that knockdown of Atg7 but not Beclin-1 attenuated the miR-100-induced LC3B-II elevation. Furthermore, miR-100 overexpression caused massive cell death, which was abrogated by both the Atg7 silencing and chloroquine treatment. Simultaneously, miR-100 expression led to increased fraction of cells with Annexin V-staining and loss of mitochondrial potential, implying that miR-100 may promote the Atg7-dependent autophagy and subsequent apoptotic cell death. Consistently, mouse xenograft models revealed that miR-100 inhibited the in vivo growth of HCC cells. We further showed that miR-100 suppressed the expression of mTOR and IGF-1R by binding to their 3′ untranslated region, and knockdown of mTOR or IGF-1R phenocopied the pro-autophagy effect of miR-100, indicating that miR-100 may promote autophagy by reducing mTOR and IGF-1R level. Collectively, our data uncover a new regulatory mechanism of autophagy and a novel function of miR-100, and provide a potential therapeutic target for HCC.