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Article first published online: 9 OCT 2012
Copyright © 2012 American Association for the Study of Liver Diseases
Volume 56, Issue 5, pages 1631–1640, November 2012
How to Cite
Zhang, Y., Wei, W., Cheng, N., Wang, K., Li, B., Jiang, X. and Sun, S. (2012), Hepatitis C virus-induced up-regulation of microRNA-155 promotes hepatocarcinogenesis by activating Wnt signaling. Hepatology, 56: 1631–1640. doi: 10.1002/hep.25849
Potential conflict of interest: Nothing to report.
Funded by Development Program (863 Program, no. 2006AA02A238) from the Ministry of Science and Technology, Development Program from the military topic (06G67), and Shanghai Municipal Natural Science Foundation (11ZR1446500).
- Issue published online: 31 OCT 2012
- Article first published online: 9 OCT 2012
- Accepted manuscript online: 18 MAY 2012 11:50AM EST
- Manuscript Accepted: 5 MAY 2012
- Manuscript Received: 12 JAN 2012
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 G0/G1 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. (HEPATOLOGY 2012;56:1631–1640)