Chang Rui-Min, Xu Jiang-Feng, Fang Feng, Yang Hao, Yang Lian-Yue
Liver Cancer Laboratory, Department of Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Liver Cancer Laboratory, Department of Surgery, Xiangya Hospital, Xiangya Road 87, Changsha, 410008, Hunan, China.
Tumour Biol. 2016 Aug;37(8):10609-19. doi: 10.1007/s13277-016-4919-z. Epub 2016 Feb 10.
Hepatocellular carcinoma (HCC) is a major cause of cancer-related deaths owing to its high rate of postoperative recurrence and metastasis. New research is continuously identifying novel metastasis-associated oncogenes and tumor suppressor genes. miRNAs are noncoding RNAs that regulate protein synthesis post-translationally. miR-130b is one of several miRNAs involved in tumor metastasis. However, the role of miR-130b in HCC remains controversial. Here, we demonstrate that miR-130b is highly expressed in HCC and that it correlates with tumor number, vascular invasion, and TNM stage-important predictors of postoperative recurrence and metastases. Moreover, high levels of miR-130b predicted poor overall and disease-free survival of HCC patients, and in vitro and in vivo research revealed that knockdown or overexpression of miR-130b inhibited and promoted proliferation and metastasis of HCC cells, respectively. We identified PTEN as a direct functional target of miR-130b using miRNA databases and a dual luciferase report assay. Next, using a gain and loss assay and epithelial-mesenchymal transition (EMT) relative assays, we show that miR-130b may promote proliferation and EMT-induced metastasis via PTEN/p-AKT/HIF-1α signaling. Collectively, our data suggests that miR-130b may have prognostic value in HCC. Additionally, the miR-130b/PTEN/p-AKT/HIF-1α axis identified in this study provides novel insight into the mechanisms of HCC metastasis, which may facilitate the development of new therapeutics against HCC.
肝细胞癌（HCC）是癌症相关死亡的主要原因之一，因其术后复发和转移率高。新的研究不断发现与转移相关的新的致癌基因和肿瘤抑制基因。miRNA是一类非编码RNA，可在翻译后调节蛋白质合成。miR-130b是参与肿瘤转移的几种miRNA之一。然而，miR-130b在HCC中的作用仍存在争议。在此，我们证明miR-130b在HCC中高表达，并且它与肿瘤数量、血管侵犯以及TNM分期相关，而TNM分期是术后复发和转移的重要预测指标。此外，高水平的miR-130b预示着HCC患者较差的总生存期和无病生存期，体外和体内研究表明，敲低或过表达miR-130b分别抑制和促进HCC细胞的增殖和转移。我们使用miRNA数据库和双荧光素酶报告基因检测法确定PTEN是miR-130b的直接功能靶点。接下来，通过功能获得和缺失实验以及上皮-间质转化（EMT）相关实验，我们表明miR-130b可能通过PTEN/p-AKT/HIF-1α信号通路促进增殖和EMT诱导的转移。总体而言，我们的数据表明miR-130b在HCC中可能具有预后价值。此外，本研究中鉴定的miR-130b/PTEN/p-AKT/HIF-1α轴为HCC转移机制提供了新的见解，这可能有助于开发针对HCC的新疗法。
