Enhanced cell survival of Hep3B cells by the hepatitis B x antigen effector, URG11, is associated with upregulation of β-catenin

Authors

  • Zhaorui Lian,

    1. Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA
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    • Zhaorui Lian and Jie Liu contributed equally to this work.

  • Jie Liu,

    1. Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA
    2. Department of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xian, China
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    • Zhaorui Lian and Jie Liu contributed equally to this work.

  • Li Li,

    1. Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA
    2. Department of General Surgery, Chengzheng Hospital, Shanghai, China
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  • Xianxing Li,

    1. Department of General Surgery, Chengzheng Hospital, Shanghai, China
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  • Marcy Clayton,

    1. Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA
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  • Meng-Chao Wu,

    1. Shanghai Eastern Hospital & Institute of Hepatobiliary Surgery, Second Military Medical University, Shanghai, China
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  • Hong-Yang Wang,

    1. Shanghai Eastern Hospital & Institute of Hepatobiliary Surgery, Second Military Medical University, Shanghai, China
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  • Patrick Arbuthnot,

    1. Molecular Hepatology Research Unit, Department of Medicine, University of the Witwatersrand, Johannesburg, South Africa
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  • Michael Kew,

    1. Molecular Hepatology Research Unit, Department of Medicine, University of the Witwatersrand, Johannesburg, South Africa
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  • Daiming Fan,

    1. Department of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xian, China
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  • Mark A. Feitelson

    Corresponding author
    1. Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA
    2. Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA
    • Room 222 Alumni Hall, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, 1020 Locust Street, Philadelphia, PA 19107
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    • fax: 215-503-9982


  • Potential conflict of interest: Nothing to report.

Abstract

Intrahepatic expression of hepatitis B x antigen (HBxAg) is associated with the development of hepatocellular carcinoma (HCC), perhaps through trans-activation of selected cellular genes. When this was examined by PowerBlot analysis, upregulated levels of β-catenin and several known β-catenin effectors were observed in HBxAg-positive compared with HBxAg-negative HepG2 cells. When HBxAg was introduced into Hep3B cells, upregulated expression of wild-type β-catenin was observed. This was also observed in Hep3B cells overexpressing the HBxAg upregulated gene, URG11. Upregulated expression of URG11 and β-catenin correlated with HBxAg trans-activation function. Transient transfection assays with fragments of the β-catenin promoter showed that it was activated by both HBxAg and URG11 and inhibited by URG11-specific small inhibitory RNA. The latter also inhibited the growth of Hep3BX cells in a serum-free medium, which correlated with depressed levels of β-catenin. Activation of β-catenin effector genes was observed in cells stably expressing HBxAg or overexpressing URG11 compared with control cells transfected with the pTOPFLASH reporter plasmid. Extensive costaining between HBxAg, URG11, and β-catenin was observed in infected liver and HCC nodules, suggesting a close relationship in vivo. In conclusion, wild-type β-catenin is activated by HBxAg, in part, through the upregulated expression of the HBxAg effector URG11. URG11 stimulates the β-catenin promoter and hepatocellular growth and survival. These observations also suggest that URG11 may be a regulatory element in the β-catenin signaling pathway and may be a target for chemoprevention of HCC. (HEPATOLOGY 2006;43:415–424.)

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