miRNA-302b Suppresses Human Hepatocellular Carcinoma by Targeting AKT2
miRNA-302b Suppresses Human Hepatocellular Carcinoma by Targeting AKT2
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miRNA-302b 通过靶向 AKT2 抑制人肝细胞癌
DOI：
10.1158/1541-7786.mcr-13-0411
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发表时间：
2014-02-01
影响因子：
5.2
通讯作者：
Huang, Chen
中科院分区：
文献类型：
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作者：
Wang, Lumin;Yao, Jiayi;Huang, Chen
mirna （miR）在包括肝细胞癌在内的人类癌症中发挥着关键作用。尽管miR-302b已被认为在其他癌症中作为肿瘤抑制因子发挥作用，但其在肝细胞癌中的作用尚不清楚。本研究探讨了miR-302b在人肝细胞癌中的表达及其功能作用。miR-302b在临床肝细胞癌标本中的表达水平与相应的非肿瘤性标本相比显著降低，在肝细胞癌细胞系中的表达水平也显著降低。在体外实验中，过表达miR-302b可抑制肝癌细胞增殖和G1-S过渡，而抑制miR-302b可促进肝癌细胞增殖和G1-S过渡。通过荧光素酶报告基因检测，AKT2被确定为miR-302b的直接靶点。随后的研究发现，在肝细胞癌组织样本中，miR-302b的表达与AKT2的表达呈负相关。重要的是，沉默AKT2再现了miR-302b过表达时的细胞和分子效应，包括抑制肝癌细胞增殖，抑制G1调节因子（Cyclin A, Cyclin D1, CDK2）和增加p27Kip1 Ser10位点的磷酸化。AKT2的恢复抵消了miR-302b表达的影响。此外，miR-302b在体内能够抑制肝癌细胞的肿瘤生长。综上所述，miR-302b在体外和体内通过靶向AKT2抑制HCC细胞的增殖和生长。Mol - Cancer Res；12 (2);190 - 202。AACR©2013。
miRNAs (miR) play a critical role in human cancers, including hepatocellular carcinoma. Although miR-302b has been suggested to function as a tumor repressor in other cancers, its role in hepatocellular carcinoma is unknown. This study investigated the expression and functional role of miR-302b in human hepatocellular carcinoma. The expression level of miR-302b is dramatically decreased in clinical hepatocellular carcinoma specimens, as compared with their respective nonneoplastic counterparts, and in hepatocellular carcinoma cell lines. Overexpression of miR-302b suppressed hepatocellular carcinoma cell proliferation and G1–S transition in vitro, whereas inhibition of miR-302b promoted hepatocellular carcinoma cell proliferation and G1–S transition. Using a luciferase reporter assay, AKT2 was determined to be a direct target of miR-302b. Subsequent investigation revealed that miR-302b expression was inversely correlated with AKT2 expression in hepatocellular carcinoma tissue samples. Importantly, silencing AKT2 recapitulated the cellular and molecular effects seen upon miR-302b overexpression, which included inhibiting hepatocellular carcinoma cell proliferation, suppressing G1 regulators (Cyclin A, Cyclin D1, CDK2) and increasing p27Kip1 phosphorylation at Ser10. Restoration of AKT2 counteracted the effects of miR-302b expression. Moreover, miR-302b was able to repress tumor growth of hepatocellular carcinoma cells in vivo. Implications: Taken together, miR-302b inhibits HCC cell proliferation and growth in vitro and in vivo by targeting AKT2. Mol Cancer Res; 12(2); 190–202. ©2013 AACR.