Intrahepatic hepatitis B virus large surface antigen induces hepatocyte hyperploidy via failure of cytokinesis

Tian Neng Li, Yi Ju Wu, Hung Wen Tsai, Cheng Pu Sun, Yi Hsuan Wu, Hui Lin Wu, Yi Ning Pei, Kuan Ying Lu, Tim Ting Chung Yen, Chien Wen Chang, Hong Lin Chan, Mi Hua Tao, Jun Yang Liou, Margaret Dah Tsyr Chang, Ih Jen Su, Lily Hui Ching Wang

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

Abstract

Hepatitis B virus (HBV) is an aetiological factor for liver cirrhosis and hepatocellular carcinoma (HCC). Despite current antiviral therapies that successfully reduce the viral load in patients with chronic hepatitis B, persistent hepatitis B surface antigen (HBsAg) remains a risk factor for HCC. To explore whether intrahepatic viral antigens contribute directly to hepatocarcinogenesis, we monitored the mitotic progression of HBV-positive cells. Cytokinesis failure was increased in HBV-positive HepG2.2.15 and 1.3ES2 cells, as well as in HuH-7 cells transfected with a wild-type or X-deficient HBV construct, but not in 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. Premitotic defects with DNA damage and G 2 /M checkpoint attenuation preceded cytokinesis in LHBS-positive cells, and ultimately resulted in hyperploidy. Inhibition of polo-like kinase-1 (Plk1) not only restored the G 2 /M checkpoint in these cells, but also suppressed LHBS-mediated in vivo tumourigenesis. Finally, a positive correlation between intrahepatic LHBS expression and hepatocyte hyperploidy was detected in >70% of patients with chronic hepatitis B. We conclude that HBV LHBS provokes hyperploidy by inducing DNA damage and upregulation of Plk1; the former results in atypical chromatin structures, and the latter attenuates the function of the G 2 /M DNA damage checkpoint. Our data uncover a mechanism by which genomic integrity of hepatocytes is disrupted by viral LHBS. These findings highlight the role of intrahepatic surface antigen as an oncogenic risk factor in the development of HCC.

Original languageEnglish
Pages (from-to)502-513
Number of pages12
JournalJournal of Pathology
Volume245
Issue number4
DOIs
Publication statusPublished - 2018 Aug

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

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