Hepatitis B virus inhibits liver regeneration via epigenetic regulation of urokinase-type plasminogen activator

Authors

  • Eun-Sook Park,

    1. Department of Pharmacology and Center for Cancer Research and Diagnostic Medicine, IBST, Konkuk University School of Medicine, Seoul, Republic of Korea
    2. Research Institute of Medical Science, Konkuk University School of Medicine, Seoul, Republic of Korea
    Search for more papers by this author
  • Yong Kwang Park,

    1. Department of Pharmacology and Center for Cancer Research and Diagnostic Medicine, IBST, Konkuk University School of Medicine, Seoul, Republic of Korea
    Search for more papers by this author
  • Chan Young Shin,

    1. Department of Pharmacology and Center for Cancer Research and Diagnostic Medicine, IBST, Konkuk University School of Medicine, Seoul, Republic of Korea
    2. Research Institute of Medical Science, Konkuk University School of Medicine, Seoul, Republic of Korea
    Search for more papers by this author
  • Seung Hwa Park,

    1. Department of Anatomy, Konkuk University School of Medicine, Seoul, Republic of Korea
    Search for more papers by this author
  • Sung Hyun Ahn,

    1. Department of Pharmacology and Center for Cancer Research and Diagnostic Medicine, IBST, Konkuk University School of Medicine, Seoul, Republic of Korea
    Search for more papers by this author
  • Doo Hyun Kim,

    1. Department of Pharmacology and Center for Cancer Research and Diagnostic Medicine, IBST, Konkuk University School of Medicine, Seoul, Republic of Korea
    Search for more papers by this author
  • Keo-Heun Lim,

    1. Department of Pharmacology and Center for Cancer Research and Diagnostic Medicine, IBST, Konkuk University School of Medicine, Seoul, Republic of Korea
    Search for more papers by this author
  • So Young Kwon,

    1. Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Republic of Korea
    Search for more papers by this author
  • Kwang Pyo Kim,

    1. Department of Molecular Biotechnology, WCU program, Konkuk University, Seoul, Republic of Korea
    Search for more papers by this author
  • Sung-Il Yang,

    1. Department of Pharmacology and Center for Cancer Research and Diagnostic Medicine, IBST, Konkuk University School of Medicine, Seoul, Republic of Korea
    Search for more papers by this author
  • Baik L. Seong,

    1. Department of Biotechnology, College of Life Science and Biotechnology, and Translational Research Center for Protein Function Control, Yonsei University, Seoul, Republic of Korea
    Search for more papers by this author
  • Kyun-Hwan Kim

    Corresponding author
    1. Department of Pharmacology and Center for Cancer Research and Diagnostic Medicine, IBST, Konkuk University School of Medicine, Seoul, Republic of Korea
    2. Research Institute of Medical Science, Konkuk University School of Medicine, Seoul, Republic of Korea
    • Address reprint requests to: Kyun-Hwan Kim, Department of Pharmacology, School of Medicine, Konkuk University, Seoul 143-701, Republic of Korea. E-mail: khkim10@kku.ac.kr; fax: +82-2-2049-6192.

    Search for more papers by this author

  • Potential conflict of interest: Nothing to report.

  • Supported in part by National Research Foundation of Korea Grant funded by the Korean Government (KRF-2008-314-C00269), a grant of the Korea Healthcare Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (Grant No. A103001).

Abstract

Liver regeneration after liver damage caused by toxins and pathogens is critical for liver homeostasis. Retardation of liver proliferation was reported in hepatitis B virus (HBV) X protein (HBx)-transgenic mice. However, the underlying mechanism of the HBx-mediated disturbance of liver regeneration is unknown. We investigated the molecular mechanism of the inhibition of liver regeneration using liver cell lines and a mouse model. The mouse model of acute HBV infection was established by hydrodynamic injection of viral DNA. Liver regeneration after partial hepatectomy was significantly inhibited in the HBV DNA-treated mice. Mechanism studies have revealed that the expression of urokinase-type plasminogen activator (uPA), which regulates the activation of hepatocyte growth factor (HGF), was significantly decreased in the liver tissues of HBV or HBx-expressing mice. The down-regulation of uPA was further confirmed using liver cell lines transiently or stably transfected with HBx and the HBV genome. HBx suppressed uPA expression through the epigenetic regulation of the uPA promoter in mouse liver tissues and human liver cell lines. Expression of HBx strongly induced hypermethylation of the uPA promoter by recruiting DNA methyltransferase (DNMT) 3A2. Conclusion: Taken together, these results suggest that infection of HBV impairs liver regeneration through the epigenetic dysregulation of liver regeneration signals by HBx. (Hepatology 2013;58:762–776)

Ancillary