Huang Da, Wang Xiaobei, Zhuang Chunbo, Shi Wuhe, Liu Mu, Tu Qiming, Zhang Detai, Hu Lihua
Department of Clinical Laboratory, Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China.
Oncol Rep. 2016 Feb;35(2):1083-90. doi: 10.3892/or.2015.4467. Epub 2015 Dec 1.
Although the tumor suppressive role of miR-101 is well documented in hepatocellular carcinoma (HCC), how the expression of miR-101 itself is regulated remains elusive. In the present study, we demonstrated that the miR-101 precursor pre-miR-101-1 could be regulated by an important epigenetic regulator, the enhancer of zeste homolog 2 (EZH2). Reporter gene assays revealed that ectopic expression of EZH2 inhibited the transcriptional activities of miR-101-1 promoter. Subsequent analyses revealed that miR-101-1 directly represses the expression of EZH2, and miR-101-1 and EZH2 form a reciprocal negative feedback loop as indicated by the fact that ectopic mature miR-101 could induce endogenous pre-miR-101-1 expression. This mature miR-101-induced pre-miR-101 expression was specific to pre-miR-101-1 and depended on EZH2 activities. Moreover, our results also demonstrated that similar antitumor effects can be achieved either by ectopic miR-101 or EZH2 silencing in HCC cells. These findings show that elevated EZH2 contributes to miR-101 deregulation in HCC and highlight the coordinated role of miR-101 and EZH2 in hepatocarcinogenesis.
尽管miR-101在肝细胞癌（HCC）中的肿瘤抑制作用已有充分记载，但其自身表达如何调控仍不清楚。在本研究中，我们证明miR-101前体pre-miR-101-1可受一种重要的表观遗传调节因子——zeste同源物2增强子（EZH2）的调控。报告基因检测显示，EZH2的异位表达抑制了miR-101-1启动子的转录活性。随后的分析表明，miR-101-1直接抑制EZH2的表达，并且miR-101-1与EZH2形成相互负反馈环，异位成熟miR-101可诱导内源性pre-miR-101-1表达这一事实表明了这一点。这种成熟miR-101诱导的pre-miR-101表达对pre-miR-101-1具有特异性，并依赖于EZH2的活性。此外，我们的结果还表明，在肝癌细胞中异位表达miR-101或沉默EZH2均可产生类似的抗肿瘤作用。这些发现表明，EZH2水平升高导致HCC中miR-101失调，并突出了miR-101和EZH2在肝癌发生中的协同作用。
