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

• Published in: The Journal of pathology 2018-08, Vol.245 (4), p.502-513
• Main Authors: Li, Tian‐Neng, Wu, Yi‐Ju, Tsai, Hung‐Wen, Sun, Cheng‐Pu, Wu, Yi‐Hsuan, Wu, Hui‐Lin, Pei, Yi‐Ning, Lu, Kuan‐Ying, Yen, Tim Ting‐Chung, Chang, Chien‐Wen, Chan, Hong‐Lin, Tao, Mi‐Hua, Liou, Jun‐Yang, Chang, Margaret Dah‐Tsyr, Su, Ih‐Jen, Wang, Lily Hui‐Ching
• Format: Article
• Language: English
• Subjects: Animals; Antigens; Antiviral agents; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Carcinoma, Hepatocellular - virology; Cell Cycle Proteins - metabolism; Cell Transformation, Viral; Chromatin; Cirrhosis; Cytokinesis; Deoxyribonucleic acid; Disease Models, Animal; DNA; DNA Damage; G2 Phase Cell Cycle Checkpoints; G2/M checkpoint; ground‐glass hepatocytes; Hep G2 Cells; Hepatitis; Hepatitis B surface antigen; Hepatitis B Surface Antigens - genetics; Hepatitis B Surface Antigens - metabolism; Hepatitis B virus - genetics; Hepatitis B virus - metabolism; Hepatitis B Virus, Woodchuck - genetics; Hepatitis B Virus, Woodchuck - metabolism; Hepatitis B, Chronic - genetics; Hepatitis B, Chronic - metabolism; Hepatitis B, Chronic - pathology; Hepatitis B, Chronic - virology; Hepatocellular carcinoma; Hepatocytes; Hepatocytes - metabolism; Hepatocytes - pathology; Hepatocytes - transplantation; Hepatocytes - virology; Host-Pathogen Interactions; Humans; Interferon; LHBS; Liver; Liver cirrhosis; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Liver Neoplasms - virology; Marmota; Mice, Transgenic; Ploidies; Polo-Like Kinase 1; polyploidy; Protein Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins - metabolism; Risk factors; Viruses
• ISSN: 0022-3417; 1096-9896
• DOI: 10.1002/path.5102

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 G2/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 G2/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 G2/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. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.