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Hepatitis B virus X induces cell proliferation in the hepatocarcinogenesis via up-regulation of cytoplasmic p21 expression

Authors

  • Masahiko Yano,

    1. Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences Niigata University, Niigata, Japan
    2. Digestive Disease Center, Showa University, Northern Yokohama Hospital, Kanagawa, Japan
    Current affiliation:
    1. Digestive Disease Center, Showa University, Northern Yokohama Hospital, Tsuzuki-ku, Kanagawa 224-8503, Japan
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  • Shogo Ohkoshi,

    Corresponding author
    1. Digestive Disease Center, Showa University, Northern Yokohama Hospital, Kanagawa, Japan
    Current affiliation:
    1. Digestive Disease Center, Showa University, Northern Yokohama Hospital, Tsuzuki-ku, Kanagawa 224-8503, Japan
    • Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences Niigata University, Niigata, Japan
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  • Yo-hei Aoki,

    1. Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences Niigata University, Niigata, Japan
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  • Hiromichi Takahashi,

    1. Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences Niigata University, Niigata, Japan
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  • Sou Kurita,

    1. Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences Niigata University, Niigata, Japan
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  • Kazuhide Yamazaki,

    1. Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences Niigata University, Niigata, Japan
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  • Kenta Suzuki,

    1. Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences Niigata University, Niigata, Japan
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  • Satoshi Yamagiwa,

    1. Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences Niigata University, Niigata, Japan
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  • Ayumi Sanpei,

    1. Division of Digestive and General Surgery, Graduate School of Medical and Dental Sciences of Niigata University, Niigata, Japan
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  • Shun Fujimaki,

    1. Department of Medical Technology, Graduate School of Health Science of Niigata University, Niigata, Japan
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  • Toshifumi Wakai,

    1. Division of Digestive and General Surgery, Graduate School of Medical and Dental Sciences of Niigata University, Niigata, Japan
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  • Shin-ei Kudo,

    1. Digestive Disease Center, Showa University, Northern Yokohama Hospital, Kanagawa, Japan
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  • Yasunobu Matsuda,

    1. Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences Niigata University, Niigata, Japan
    2. Department of Medical Technology, Graduate School of Health Science of Niigata University, Niigata, Japan
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  • Yutaka Aoyagi

    1. Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences Niigata University, Niigata, Japan
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Correspondence

Shogo Ohkoshi, Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences of Niigata University, 1-754 Asahimachi – Dori, Chuo-ku, Niigata 951-8122, Japan

Tel: +81 25 227 2204

Fax: +81 25 227 0776

e-mail: okoshi@med.showa-u.ac.jp

Abstract

Background

Hepatitis B virus X protein (HBx) has been shown to induce hepatocarcinogenesis by disrupting the functions of intracellular molecules. Cyclin-dependent kinase inhibitor p21 (Cip1/WAF1), known as a tumour-suppressor gene, has been reported to have paradoxical function, that is, acting as an oncogene, particularly when expressed in the cytoplasm. The effects of HBx on the expression and function of p21 also remain controversial.

Aims

We attempted to investigate the role of HBx in the hepatocarcinogenic process, focusing on the association with this paradoxical function of p21. The results obtained were further verified with experiments using the antihepatocarcinogenic action of interferon (IFN)-β.

Methods

HBx transgenic mice (Xg) and HBx-transfected hepatoma cell lines were used. Intracellular localization of p21 was determined by Western blot analysis and immunofluorescence.

Results

Xg and HBx-transfected cells exhibited increased expression of p21. Up-regulation of p21 was positively correlated with the expression of cyclin D1 and inactive phosphorylation of retinoblastoma protein (pRb). These HBx-induced cell proliferative responses were cancelled by knockdown of p21, which resulted in growth reduction in HBx-expressing cells, suggesting the oncogenic properties of HBx-induced p21. HBx induced accumulation of p21 in the cytoplasm, and activation of PKCα was involved. Finally, IFN-β-treated Xg liver, as well as hepatoma cells, showed a shift of cytoplasmic p21 to the nucleus, accompanied by the abrogation of HBx-induced oncogenic modulation.

Conclusions

Our results suggest that HBx induces hepatocarcinogenesis via PKCα-mediated overexpression of cytoplasmic p21 and IFN-β suppressed these molecular events by shifting p21 to the nucleus.

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