Citation

  • Authors: Zhang, Y., Wei, W., Cheng, N., Wang, K., Li, B., Jiang, X., Sun, S.
  • Year: 2012
  • Journal: Hepatology 56 1631-40
  • Applications: in vitro / miRNA plasmid / jetPEI-Hepatocyte
  • Cell types:
    1. Name: Hepatocytes
      Description: Hepatocyte cells.
    2. Name: Huh7
      Description: Human hepatocarcinoma cells
      Known as: Huh7, Huh 7

Abstract

UNLABELLED: 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-kappaB), and p300 increased NF-kappaB-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 beta-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.

Pubmed