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

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A Correction to this article was published on 04 November 2021

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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.

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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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Authors and Affiliations

  1. The Second Affiliated Hospital, Chongqing Medical University, Lin Jiang Road, No.74, Chongqing, 400010, Chongqing, China

    Jiao Liu, Zengchan Wang, Jia Tang, Renkuan Tang, Xiaoliang Shan, Wenlu Zhang, Qingmei Chen, Fan Zhou, Ke Chen, Ailong Huang & Ni Tang

  2. Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Yixueyuan Road, No.1, Chongqing, 400016, Chongqing, China

    Jiao Liu, Zengchan Wang, Jia Tang, Renkuan Tang, Xiaoliang Shan, Wenlu Zhang, Qingmei Chen, Fan Zhou, Ke Chen, Ailong Huang & Ni Tang

  3. Department of Forensic Medicine, Chongqing Medical University, Chongqing, China

    Renkuan Tang

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  1. Jiao Liu
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  2. Zengchan Wang
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  3. Jia Tang
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  11. Ni Tang
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Correspondence to Ailong Huang or Ni Tang.

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J. Liu and Z. Wang contributed equally to this study.

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Liu, J., Wang, Z., Tang, J. et al. Hepatitis C virus core protein activates Wnt/β-catenin signaling through multiple regulation of upstream molecules in the SMMC-7721 cell line. Arch Virol 156, 1013–1023 (2011). https://doi.org/10.1007/s00705-011-0943-x

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