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Hepatitis B x antigen up-regulates vascular endothelial growth factor receptor 3 in hepatocarcinogenesis

Authors

  • Zhaorui Lian,

    1. Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA
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    • These authors contributed equally to this work.

  • Jie Liu,

    1. Department of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032 China
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    • These authors contributed equally to this work.

  • Mengchao Wu,

    1. Shanghai Eastern Hospital & Institute of Hepatobiliary Surgery, Second Military Medical University, Shanghai 200438 China
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  • Hong-Yang Wang,

    1. Shanghai Eastern Hospital & Institute of Hepatobiliary Surgery, Second Military Medical University, Shanghai 200438 China
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  • Patrick Arbuthnot,

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

    1. Molecular Hepatology Research Unit, Department of Medicine, University of the Witwatersrand, Johannesburg
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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

Hepatitis B x antigen (HBxAg) is a trans-activating protein that contributes to liver cancer, in part, by altering the expression of cellular genes. However, few natural effectors of HBxAg have been identified. Hence, HBxAg positive and negative HepG2 cells were prepared and analyzed by PCR select cDNA subtraction. The results identified elevated vascular endothelial growth factor receptor-3 short form splice variant (VEGFR-3S) expression in HBxAg positive compared to negative cells. Normally, VEGFR-3 activates Akt signaling in lymphatic endothelial cells, resulting in lymphangiogenesis. In contrast, the results here show that the expression of VEGFR-3S is up-regulated in >75% of HBxAg positive hepatocellular carcinoma (HCC) nodules. VEGFR-3S up-regulation correlates with the expression of HBxAg, is associated with decreased survival in tumor bearing patients, and when over-expressed in HepG2 cells, strongly stimulated cell growth in culture, in soft agar, and accelerated tumor formation in a ligand independent manner. VEGFR-3S siRNA partially blocked the ability of HBxAg to promote hepatocellular growth. In conclusion, HBxAg may short circuit VEGFR-3S signaling in liver cancer. Blocking VEGFR-3S signaling may be effective in preventing tumor development and/or prolonging survival in tumor bearing patients. (HEPATOLOGY 2007;45:1390–1399.)

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