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Hepatitis C virus‐induced up‐regulation of microRNA‐155 promotes hepatocarcinogenesis by activating Wnt signaling
Author(s) -
Zhang Yiliang,
Wei Wei,
Cheng Na,
Wang Kaihui,
Li Bin,
Jiang Xiaoqing,
Sun Shuhan
Publication year - 2012
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.25849
Subject(s) - wnt signaling pathway , carcinogenesis , mir 155 , cancer research , inflammation , biology , hepatocyte , microrna , survivin , signal transduction , apoptosis , immunology , medicine , cancer , microbiology and biotechnology , in vitro , biochemistry , gene
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. Conclusion : 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. (H EPATOLOGY 2012;56:1631–1640)