title: microRNA-539 suppresses tumor growth and tumorigenesis and overcomes arsenic trioxide resistance in hepatocellular carcinoma.
abstract: OBJECTIVE
  Dysregulation of microRNAs (miRNAs) plays a critical role in tumor growth and progression. In this study, we sought to explore the expression and biological roles of miR-539 in hepatocellular carcinoma (HCC).
  
  
  METHODS
  The expression of miR-539 in human HCC tissues and cell lines was examined. The effects of miR-539 overexpression on cell growth, tumorigenicity, arsenic trioxide resistance of HCC cells were determined. The signaling pathways involved in the action of miR-539 in HCC were also investigated.
  
  
  RESULTS
  miR-539 was downregulated in HCC tissues and cells, relative to corresponding controls. Overexpression of miR-539 inhibited HCC cell viability and colony formation in vitro and impaired tumorigenesis of HCC cells in vivo. Transfection with miR-539 mimic significantly induced apoptosis in HepG2 cells, which was coupled with reduced expression of anti-apoptotic proteins Bcl-2 and Bcl-xL and decreased phosphorylation of Stat3. Overexpression of a constitutively active form of Stat3 partially blocked miR-539-mediated apoptosis. Enforced expression of miR-539 resensitized arsenic trioxide-resistant HCC cells to arsenic trioxide. Intratumoral delivery of miR-539 mimic significantly retarded the growth of xenograft tumors from arsenic trioxide-resistant HCC cells by about 35%, compared to delivery of control miRNA (P<0.05). In combination with arsenic trioxide, miR-539 mimic yielded about 80% decrease in tumor burden.
  
  
  CONCLUSIONS
  miR-539 functions as a tumor suppressor in HCC and reexpression of this miRNA offers a potential therapeutic strategy for this disease.
authors.affiliation: Department of Oncology, Xin Hua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Chuanying
authors.initials: C
authors.lastname: Zhu
authors.affiliation: Department of Oncology, Xin Hua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Renhua
authors.initials: R
authors.lastname: Zhou
authors.affiliation: Department of Oncology, Xin Hua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: Department of Orthopaedics and Traumatology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Yuewen
authors.initials: Y
authors.lastname: Chang
authors.affiliation: Department of Oncology, Xin Hua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China. Electronic address: xiaojiangchengsun@163.com.
authors.forename: Mawei
authors.initials: M
authors.lastname: Jiang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology / Q000627:therapeutic use*; D063646:Carcinogenesis / Q000187:drug effects / Q000235:genetics / Q000473:pathology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D010087:Oxides / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; C552081:MIRN539 microRNA, human; D035683:MicroRNAs; D010087:Oxides; D000077237:Arsenic Trioxide
keywords: Apoptosis; Chemoresistance; Growth; Stat3 activation; microRNA