國家衛生研究院 NHRI:Item 3990099045/11216
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    题名: Intrahepatic hepatitis B virus large surface antigen induces hepatocyte hyperploidy via failure of cytokinesis
    作者: Li, TN;Wu, YJ;Tsai, HW;Sun, CP;Wu, YH;Wu, HL;Pei, YN;Lu, KY;Yen, TT;Chang, CW;Chan, HL;Tao, MH;Liou, JY;Chang, MD;Su, IJ;Wang, LH
    贡献者: Institute of Cellular and Systems Medicine
    摘要: Hepatitis B virus (HBV) is an etiological factor of liver cirrhosis and hepatocellular carcinoma (HCC). Despite current antiviral therapies that successfully reduce viral load in patients with chronic hepatitis B, persistent viral surface antigen (HBsAg) remains a risk factor of HCC. To explore if intrahepatic viral antigens contribute directly to hepatocarcinogenesis, we monitored mitotic progression of HBV-positive cells. Cytokinesis failure was increased in HBV-positive HepG2.2.15 and 1.3ES2 cells, as well as HuH-7 cells transfected with wild type or X-deficient HBV construct, but not cells transfected with an HBsAg-deficient construct. We show that expression of viral large surface antigen (LHBS) was sufficient to induce cytokinesis failure of immortalized hepatocytes. Pre-mitotic defects with DNA damage and G2/M checkpoint attenuation preceded cytokinesis in LHBS-expressing cells, and ultimately resulted in hyperploidy. Inhibition of polo-like kinase-1 (Plk1) not only restored the G2/M checkpoint in these cells, but also suppressed LHBS-mediated in vivo tumorigenesis. Finally, a positive correlation between intrahepatic LHBS expression and hepatocyte hyperploidy was detected in more than 70% of patients with chronic hepatitis B. We conclude that HBV LHBS provokes hyperploidy through inducing DNA damage and the upregulation of Plk1; the former causes atypical chromatin structures and the latter attenuates function of the G2/M DNA damage checkpoint. Our data uncover a mechanism whereby mitotic cytokinesis can be regulated by viral LHBS, warranting intrahepatic LHBS as an oncogenic caveat for the development of HCC in patients with chronic hepatitis B.
    日期: 2018-08
    關聯: Journal of Pathology. 2018 Aug;245(5):502-513.
    Link to: http://dx.doi.org/10.1002/path.5102
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0022-3417&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000438654600011
    Cited Times(Scopus): https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85049943324
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