title: MicroRNA-26a suppresses tumor growth and metastasis of human hepatocellular carcinoma by targeting interleukin-6-Stat3 pathway.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors: Liver Cancer Institute and Zhongshan Hospital, Institutes of Biomedical Science, Fudan University, Shanghai, China.
authors: Xin
authors: X
authors: Yang
authors: Lei
authors: L
authors: Liang
authors: Xiao-Fei
authors: XF
authors: Zhang
authors: Hu-Liang
authors: HL
authors: Jia
authors: Yi
authors: Y
authors: Qin
authors: Xu-Chao
authors: XC
authors: Zhu
authors: Xiao-Mei
authors: XM
authors: Gao
authors: Peng
authors: P
authors: Qiao
authors: Yan
authors: Y
authors: Zheng
authors: Yuan-Yuan
authors: YY
authors: Sheng
authors: Jin-Wang
authors: JW
authors: Wei
authors: Hai-Jun
authors: HJ
authors: Zhou
authors: Ning
authors: N
authors: Ren
authors: Qing-Hai
authors: QH
authors: Ye
authors: Qiong-Zhu
authors: QZ
authors: Dong
authors: Lun-Xiu
authors: LX
authors: Qin
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology* / Q000556:secondary; D015536:Down-Regulation; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism* / Q000494:pharmacology; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology* / Q000556:secondary; D008297:Male; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000627:therapeutic use*; D008875:Middle Aged; D050796:STAT3 Transcription Factor / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D015850:Interleukin-6; D035683:MicroRNAs; D050796:STAT3 Transcription Factor; C528163:MIRN26 microRNA, human