title: Primate-specific microRNA-637 inhibits tumorigenesis in hepatocellular carcinoma by disrupting signal transducer and activator of transcription 3 signaling.
abstract: MiR-637 (microRNA-637) is a primate-specific miRNA belonging to the small noncoding RNA family, which represses gene regulation at the post-transcriptional expression level. Although it was discovered approximately 5 years ago, its biomedical significance and regulatory mechanism remain obscure. Our preliminary data showed that miR-637 was significantly suppressed in four HCC cell lines and, also, in most of the hepatocellular carcinoma (HCC) specimens, thereby suggesting that miR-637 would be a tumor suppressor in HCC. Simultaneously, the enforced overexpression of miR-637 dramatically inhibited cell growth and induced the apoptosis of HCC cells. The transcription factor, signal transducer and activator of transcription 3 (Stat3), is constitutively activated in multiple tumors, and aberrant Stat3 activation is linked to the promotion of growth and desensitization of apoptosis. Our study showed that Stat3 tyrosine 705 phosphorylation and several Stat3-regulated antiapoptotic genes were down-regulated in miR-637 mimics-transfected and Lv-miR637-infected HCC cells. In addition, miR-637 overexpression negatively regulated Stat3 phosphorylation by suppressing autocrine leukemia inhibitory factor (LIF) expression and exogenous LIF-triggered Stat3 activation and rescued cell growth in these cells. A nude mice model also demonstrated the above-described results, which were obtained from the cell model. Furthermore, we found that LIF was highly expressed in a large proportion of HCC specimens, and its expression was inversely associated with miR-637 expression.
  
  
  CONCLUSIONS
  Our data indicate that miR-637 acted as a tumor suppressor in HCC, and the suppressive effect was mediated, at least in part, by the disruption of Stat3 activation.
authors.affiliation: Stanley Ho Center for Emerging Infectious Diseases, the Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Jin-fang
authors.initials: JF
authors.lastname: Zhang
authors.forename: Ming-liang
authors.initials: ML
authors.lastname: He
authors.forename: Wei-ming
authors.initials: WM
authors.lastname: Fu
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.forename: Lian-zhou
authors.initials: LZ
authors.lastname: Chen
authors.forename: Xiao
authors.initials: X
authors.lastname: Zhu
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.forename: Dan
authors.initials: D
authors.lastname: Xie
authors.forename: Paul
authors.initials: P
authors.lastname: Lai
authors.forename: Gong
authors.initials: G
authors.lastname: Chen
authors.forename: Gang
authors.initials: G
authors.lastname: Lu
authors.forename: Marie C M
authors.initials: MC
authors.lastname: Lin
authors.forename: Hsiang-fu
authors.initials: HF
authors.lastname: Kung
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000503:physiopathology*; D049108:Cell Enlargement / Q000187:drug effects; D045744:Cell Line, Tumor; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D053605:Leukemia Inhibitory Factor / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000187:drug effects; D008113:Liver Neoplasms / Q000235:genetics / Q000503:physiopathology*; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis / Q000502:physiology*; D011323:Primates; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects*; D015854:Up-Regulation
chemical_list: D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; C569538:MIRN637 microRNA, human; D035683:MicroRNAs; D050796:STAT3 Transcription Factor