Co-targeting of IGF1R/mTOR pathway by miR-497 and miR-99a impairs hepatocellular carcinoma development.
Co-targeting of IGF1R/mTOR pathway by miR-497 and miR-99a impairs hepatocellular carcinoma development.
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miR-497 和 miR-99a 共同靶向 IGF1R/mTOR 通路损害肝细胞癌的发展
DOI：
10.18632/oncotarget.18207
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发表时间：
2017-07-18
期刊：
影响因子：
--
通讯作者：
Wang G
中科院分区：
文献类型：
--
作者：
Cheng H;Xue J;Yang S;Chen Y;Wang Y;Zhu Y;Wang X;Kuang D;Ruan Q;Duan Y;Wang G
IGF 1 R/mTOR信号通路的持续激活在肝细胞癌（HCC）的发生发展中起着至关重要的作用。因此，我们的目标是阐明靶向IGF 1 R/mTOR的microRNAs（miRNAs）以及单个或双miRNA对HCC发展的治疗潜力。在这项研究中，我们发现靶向IGF 1 R和mTOR的3′-UTR的miR-497和miR-99 a在HCC组织和细胞系中下调。功能分析显示，miR-497或miR-99 a在HCC细胞中的异位表达可通过抑制IGF 1 R和mTOR的表达，显著抑制肿瘤的体外生长和侵袭能力以及体内肿瘤的发展。这种对肿瘤生长的抑制作用通过体外应用IGF 1（IGF 1 R配体）或MHY 1485（mTOR激动剂）逆转。此外，我们发现同时过表达miR-497和miR-99 a对肿瘤生长的抑制作用比它们各自的作用强得多，这仍然与IGF 1 R和mTOR的显著更强的抑制相关。总之，我们的研究结果表明，miR-497和miR-99 a都是通过抑制IGF 1 R/mTOR信号通路发挥肿瘤抑制作用的miRNA。这两种miRNAs的协同作用与IGF 1 R和mTOR水平部分相关，这可能代表HCC分子治疗的新策略。
Persistent activation of IGF1R/mTOR signaling pathway plays crucial role in the development of hepatocellular carcinoma (HCC). Therefore, our goal was to elucidate microRNAs (miRNAs) targeting IGF1R/mTOR and the therapeutic potential of single or dual miRNA on HCC development. In this study, we found that miR-497 and miR-99a that target the 3′-UTR of both IGF1R and mTOR were down-regulated in HCC human tissues and cell lines. Functional assay revealed that ectopic expression of miR-497 or miR-99a in HCC cells resulted in a significant inhibition on tumor growth and invasiveness in vitro and tumor development in vivo via repressing the expression of IGF1R and mTOR. Such inhibitory effect on tumor growth is reversed by application of IGF1 ((IGF1R ligand) or MHY1485 (mTOR agonist) in vitro. Furthermore, we found that simultaneous over-expression of both miR-497 and miR-99a exhibited much stronger inhibitory effects on tumor growth than their individual effect, which is still correlated with significantly stronger repression of IGF1R and mTOR. Overall, our results suggest that miR-497 and miR-99a both function as tumor-suppressive miRNAs by suppressing IGF1R/mTOR signaling pathway. The synergistic actions of these two miRNAs partly correlated with IGF1R and mTOR levels, which may represent new strategies for the molecular treatment of HCC.
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DOI：
10.1038/mt.2016.9
发表时间：
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