title: Hepatitis C virus-induced up-regulation of microRNA-155 promotes hepatocarcinogenesis by activating Wnt signaling.
abstract: Hepatitis C virus (HCV) infection usually induces chronic hepatic inflammation, which favors the initiation and progression of hepatocellular carcinoma (HCC). Moreover, microRNA-155 (miR-155) plays an important role in regulating both inflammation and tumorigenesis. However, little is known about whether and how miR-155 provides the link between inflammation and cancer. In this study we found that miR-155 levels were markedly increased in patients infected with HCV. MiR-155 transcription was regulated by nuclear factor kappa B (NF-κB), and p300 increased NF-κB-dependent miR-155 expression. The overexpression of miR-155 significantly inhibited hepatocyte apoptosis and promoted cell proliferation, whereas miR-155 inhibition induced G(0) /G(1) arrest. Up-regulated miR-155 resulted in nuclear accumulation of β-catenin and a concomitant increase in cyclin D1, c-myc, and survivin. Gain-of-function and loss-of-function studies demonstrated that miR-155 promoted hepatocyte proliferation and tumorigenesis by increasing Wnt signaling in vitro and in vivo, and DKK1 (Wnt pathway inhibitor) overexpression inhibited the biological role of miR-155 in hepatocytes. Finally, adenomatous polyposis coli (APC), which negatively regulates Wnt signaling, was identified as the direct and functional target of miR-155.
  
  
  CONCLUSIONS
  HCV-induced miR-155 expression promotes hepatocyte proliferation and tumorigenesis by activating Wnt signaling. The present study provides a better understanding of the relationship between inflammation and tumorigenesis, and thus may be helpful in the development of effective diagnosis and treatment strategies against HCV-HCC.
authors.affiliation: Department of Medical Genetics, Secondary Military Medicine University, Shanghai, China.
authors.forename: Yiliang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.forename: Na
authors.initials: N
authors.lastname: Cheng
authors.forename: Kaihui
authors.initials: K
authors.lastname: Wang
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Jiang
authors.forename: Shuhan
authors.initials: S
authors.lastname: Sun
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000818:Animals; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D054357:Chemokine CXCL10 / Q000097:blood; D019938:Cyclin D1 / Q000378:metabolism; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints; D016174:Hepacivirus; D019698:Hepatitis C, Chronic / Q000097:blood / Q000378:metabolism*; D022781:Hepatocytes; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D012367:RNA, Viral / Q000378:metabolism; D000077022:Survivin; D014162:Transfection; D015854:Up-Regulation; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism; D050880:p300-CBP Transcription Factors / Q000378:metabolism
chemical_list: D025601:Adenomatous Polyposis Coli Protein; C107489:BIRC5 protein, human; C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; C501126:DKK1 protein, human; D051034:Inhibitor of Apoptosis Proteins; D036341:Intercellular Signaling Peptides and Proteins; C524942:MIRN155 microRNA, human; C489427:MYC protein, human; D035683:MicroRNAs; D016328:NF-kappa B; D016271:Proto-Oncogene Proteins c-myc; D012367:RNA, Viral; D000077022:Survivin; D051176:beta Catenin; D019938:Cyclin D1; D050880:p300-CBP Transcription Factors