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Archives of Virology

, Volume 156, Issue 6, pp 1013–1023 | Cite as

Hepatitis C virus core protein activates Wnt/β-catenin signaling through multiple regulation of upstream molecules in the SMMC-7721 cell line

  • Jiao Liu
  • Zengchan Wang
  • Jia Tang
  • Renkuan Tang
  • Xiaoliang Shan
  • Wenlu Zhang
  • Qingmei Chen
  • Fan Zhou
  • Ke Chen
  • Ailong Huang
  • Ni Tang
Original Article

Abstract

The core protein of hepatitis C virus (HCV) has been implicated in HCV-induced liver pathogenesis. Previous data have shown that the HCV core protein has pleiotropic functions, including transcriptional regulation of a number of cellular genes, although the mechanism of gene regulation remains unclear. Wnt/β-catenin signaling is also involved in hepatocellular carcinoma (HCC) tumorigenesis. To elucidate the molecular mechanism of HCV pathogenesis, we examined whether HCV core protein activates Wnt/β-catenin signaling in the hepatoma cell line SMMC-7721. The effects of core protein on Wnt/β-catenin signaling cascades were investigated by luciferase reporter gene assay, immunofluorescence, western blot and RT-PCR analysis. Here, we demonstrate that HCV core protein plays an essential role in activating β-catenin/Tcf-4-dependent transcriptional activity and increases active β-catenin expression and nuclear accumulation in SMMC-7721 cells. An RT-PCR assay indicated that core protein upregulates gene expression of canonical Wnt ligands, such as Wnt2, Wnt3, Wnt3a, Wnt8b, Wnt10a, Wnt10b, frizzled receptors Fzd1, 2, 5, 6, 7, 9, and LRP5/6 co-receptors. However, Wnt antagonists SFRP3, 5 and Dkk1 were moderately repressed. Furthermore, ectopic expression of core protein markedly promoted cell proliferation. The soluble Fzd molecule FrzB or the β-catenin inhibitor siBC efficiently blocked cell growth stimulation by the core gene. Our present findings demonstrate that the HCV core protein activates canonical Wnt signaling through tight regulation of several important molecules upstream of β-catenin and presumably results in promotion of cell proliferation in the SMMC-7721 cell line. Taken together, these data suggested that the core protein may be directly involved in Wnt/β-catenin-mediated liver pathogenesis.

Keywords

Core Protein Frizzle Receptor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

We thank Dr. Jianming Hu of The Pennsylvania State University College of Medicine, USA, for critical reading of the manuscript, Dr. Charles M. Rice of Rockefeller University, USA, for kind provision of plasmid HFL, Dr. T.-C He of University of Chicago, USA, for kind provision of plasmid pTop-luc and adenoviruses expressing Wnt3A, FrzB and siBC. This work was supported by research grants from China National Natural Science Foundation (#30972586, NT), Natural Science Foundation Project of CQ CSTC (2009BA5036, NT), Natural Science Foundation Project of CQMU (NT) and Major National S&T program (2008ZX10001-016, ALH).

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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Jiao Liu
    • 1
    • 2
  • Zengchan Wang
    • 1
    • 2
  • Jia Tang
    • 1
    • 2
  • Renkuan Tang
    • 1
    • 2
    • 3
  • Xiaoliang Shan
    • 1
    • 2
  • Wenlu Zhang
    • 1
    • 2
  • Qingmei Chen
    • 1
    • 2
  • Fan Zhou
    • 1
    • 2
  • Ke Chen
    • 1
    • 2
  • Ailong Huang
    • 1
    • 2
  • Ni Tang
    • 1
    • 2
  1. 1.The Second Affiliated HospitalChongqing Medical UniversityChongqingChina
  2. 2.Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of EducationChongqing Medical UniversityChongqingChina
  3. 3.Department of Forensic MedicineChongqing Medical UniversityChongqingChina

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