C-terminal truncated hepatitis B virus x protein is associated with metastasis and enhances invasiveness by c-jun/matrix metalloproteinase protein 10 activation in hepatocellular carcinoma

Authors

  • Karen M.F. Sze,

    1. State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong
    2. Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
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  • Glanice K.Y. Chu,

    1. State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong
    2. Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
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  • Joyce M.F. Lee,

    1. State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong
    2. Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
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  • Irene O.L. Ng

    Corresponding author
    1. State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong
    2. Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
    • Department of Pathology, The University of Hong Kong, Queen Mary Hospital, University Pathology Building, Room 127B, Pokfulam, Hong Kong
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    • fax: 852-2872-5197


  • Potential conflict of interest: Nothing to report.

  • The study was funded by the Hong Kong Research Fund for the Control of Infectious Diseases (05050022), the Hong Kong Research Grants Council Collaborative Research Fund (HKU 1/06C and 7/CRF/09), and the Hong Kong University Small Project Fund (200707176172). I.O.L.N. is Loke Yew Professor in Pathology.

Abstract

Random integration of hepatitis B virus (HBV) DNA into the host genome is frequent in human hepatocellular carcinoma (HCC) and this leads to truncation of the HBV DNA, particularly at the C-terminal end of the HBV X protein (HBx). In this study, we investigated the frequency of this natural C-terminal truncation of HBx in human HCCs and its functional significance. In 50 HBV-positive patients with HCC, full-length HBx was detected in all nontumorous livers. However, full-length HBx was found in only 27 (54%) of the HCC tumors, whereas natural carboxylic acid (COOH)-truncated HBx was found in the remaining 23 (46%) tumors. Upon clinicopathological analysis, the presence of natural COOH-truncated HBx significantly correlated with the presence of venous invasion, a hallmark of metastasis (P = 0.005). Inducible stable expression of the COOH-truncated HBx protein (with 24 amino acids truncated at the C-terminal end) enhanced the cell-invasive ability of HepG2 cells, as compared to full-length HBx, using the Matrigel cell-invasion assay. It also resulted in increased C-Jun transcriptional activity and enhanced transcription of matrix metalloproteinase 10 (MMP10), whereas activation of the MMP10 promoter by COOH-truncated HBx was abolished when the activator protein 1–binding sites on the MMP10 promoter were mutated. Furthermore, silencing of MMP10 by short interfering RNA in HBxΔC1-expressing HepG2 cells resulted in significant reduction of cell invasiveness. Conclusions: Our data suggest that COOH truncation of HBx, particularly with 24 amino acids truncated at the C-terminal end, plays a role in enhancing cell invasiveness and metastasis in HCC by activating MMP10 through C-Jun. (HEPATOLOGY 2013)

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