MicroRNA-26a Suppresses Tumor Growth and Metastasis of Human Hepatocellular Carcinoma by Targeting Interleukin-6-Stat3 Pathway

作者：Yang, Xin; Liang, Lei; Zhang, Xiao-Fei; Jia, Hu-Liang; Qin, Yi; Zhu, Xu-Chao; Gao, Xiao-Mei; Qiao, Peng; Zheng, Yan; Sheng, Yuan-Yuan; Wei, Jin-Wang; Zhou, Hai-Jun; Ren, Ning; Ye, Qing-Hai; Dong, Qiong-Zhu; Qin, Lun-Xiu^*

来源：Hepatology, 2013, 58(1): 158-170.

DOI：10.1002/hep.26305

• HUMAN LIVER-CANCER
• CELL-GROWTH
• STEM-CELLS
• IN-VIVO
• EXPRESSION
• MIR-26A
• STAT3
• ACTIVATION
• APOPTOSIS
• EZH2

Down-regulation of microRNA-26a (miR-26a) is associated with poor prognosis of hepatocellular carcinoma (HCC), but its functional mechanism in HCC remains unclear. In this study, we investigated the roles of miR-26a in tumor growth and metastasis of HCC and found that miR-26a was frequently down-regulated in HCC tissues. Down-regulation of miR-26a correlated with HCC recurrence and metastasis. Through gain-and loss-of-function studies, miR-26a was demonstrated to significantly inhibit in vitro cell proliferation, migration, and invasion. In addition, miR-26a induced G1 arrest and promoted apoptosis of HCC cells. Importantly, miR-26a suppressed in vivo tumor growth and metastasis in nude mice models bearing human HCC. Interleukin-6 (IL-6) was identified as a target of miR-26a. Knockdown of IL-6 induced effects on HCC cells similar to those induced by miR-26a. In contrast, IL-6 treatment abrogated the effects induced by miR-26a up-regulation. Moreover, miR-26a dramatically suppressed expression of signal transducer and activator of transcription 3 (Stat3) target genes, including Bcl-2, Mcl-1, cyclin D1, and MMP2. IL-6 treatment antagonized this effect, while knockdown of IL-6 by IL-6 short hairpin RNA (shIL-6) induced inhibitory effects on the expression of p-Stat3 and its main target genes, similar to miR-26a. The messenger RNA and protein levels of IL-6 inversely correlated with miR-26a in HCCs. Patients with high miR-26a or low IL-6 in HCC tissues had a better prognosis with longer overall survival (OS) and time to recurrence (TTR). In multivariate analysis, miR-26a, IL-6, and their combination were demonstrated to be independent prognostic indicators for OS and TTR of HCC patients. Conclusion: miR-26a could suppress tumor growth and metastasis of HCC through IL-6-Stat3 signaling and is a novel prognostic marker and therapeutic target for HCC.

• 出版日期2013-7
• 单位复旦大学