@article{8dc1bbe4050144c8a7e52b4f3ead770d,
title = "Intrahepatic hepatitis B virus large surface antigen induces hepatocyte hyperploidy via failure of cytokinesis",
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.",
author = "Li, {Tian Neng} and Wu, {Yi Ju} and Tsai, {Hung Wen} and Sun, {Cheng Pu} and Wu, {Yi Hsuan} and Wu, {Hui Lin} and Pei, {Yi Ning} and Lu, {Kuan Ying} and Yen, {Tim Ting Chung} and Chang, {Chien Wen} and Chan, {Hong Lin} and Tao, {Mi Hua} and Liou, {Jun Yang} and Chang, {Margaret Dah Tsyr} and Su, {Ih Jen} and Wang, {Lily Hui Ching}",
note = "Funding Information: We thank all Wang laboratory members and Dr Wenya Huang for helpful comments and discussions. We thank the Biomedical Centre of National Tsing Hua University for microscopy support. We thank Dr Ning-Shao Xia for providing research reagents. We also thank Mr Salix Lin from Major Instruments Taiwan for helping with ASI chromosome karyotyping. This work was supported by grants to LHCW and IJS from the Taiwan Ministry of Science and Technology (MOST-104-2320-B-007-003 and MOST-105-2320-B-007-006-MY3 to LHCW; MOST-104-2320-B-218-002-MY3 to IJS) and National Tsing Hua University. We also thank the Programme for Translational Innovation of Biopharmaceutical Development – Technology Supporting Platform Axis (Grant No. 107-0210-01-19-04) for technical support. Funding Information: We thank all Wang laboratory members and Dr Wenya Huang for helpful comments and discussions. We thank the Biomedical Centre of National Tsing Hua University for microscopy support. We thank Dr Ning-Shao Xia for providing research reagents. We also thank Mr Salix Lin from Major Instruments Taiwan for helping with ASI chromosome karyotyping. This work was supported by grants to LHCW and IJS from the Taiwan Ministry of Science and Technology (MOST-104-2320-B-007-003 and MOST-105-2320-B-007-006-MY3 to LHCW; MOST-104-2320-B-218-002-MY3 to IJS) and National Tsing Hua University. We also thank the Programme for Translational Innovation of Biopharmaceutical Development – Technology Supporting Platform Axis (Grant No. 107-0210-01-19-04) for technical support. Publisher Copyright: Copyright {\textcopyright} 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.",
year = "2018",
month = aug,
doi = "10.1002/path.5102",
language = "English",
volume = "245",
pages = "502--513",
journal = "Journal of Pathology",
issn = "0022-3417",
publisher = "John Wiley and Sons Ltd",
number = "4",
}
