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

研究成果: Article

3 引文 (Scopus)

摘要

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.

原文English
頁(從 - 到)502-513
頁數12
期刊Journal of Pathology
245
發行號4
DOIs
出版狀態Published - 2018 八月

指紋

Cytokinesis
Surface Antigens
Hepatitis B virus
Hepatocytes
DNA Damage
Hepatocellular Carcinoma
Chronic Hepatitis B
Hepatitis B Surface Antigens
Viral Antigens
Viral Load
Liver Cirrhosis
Chromatin
Antiviral Agents
Up-Regulation

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

引用此文

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. / Intrahepatic hepatitis B virus large surface antigen induces hepatocyte hyperploidy via failure of cytokinesis. 於: Journal of Pathology. 2018 ; 卷 245, 編號 4. 頁 502-513.
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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}",
year = "2018",
month = "8",
doi = "10.1002/path.5102",
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Li, TN, Wu, YJ, Tsai, HW, Sun, CP, Wu, YH, Wu, HL, Pei, YN, Lu, KY, Yen, TTC, Chang, CW, Chan, HL, Tao, MH, Liou, JY, Chang, MDT, Su, IJ & Wang, LHC 2018, 'Intrahepatic hepatitis B virus large surface antigen induces hepatocyte hyperploidy via failure of cytokinesis', Journal of Pathology, 卷 245, 編號 4, 頁 502-513. https://doi.org/10.1002/path.5102

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

於: Journal of Pathology, 卷 245, 編號 4, 08.2018, p. 502-513.

研究成果: Article

TY - JOUR

T1 - Intrahepatic hepatitis B virus large surface antigen induces hepatocyte hyperploidy via failure of cytokinesis

AU - Li, Tian Neng

AU - Wu, Yi Ju

AU - Tsai, Hung Wen

AU - Sun, Cheng Pu

AU - Wu, Yi Hsuan

AU - Wu, Hui Lin

AU - Pei, Yi Ning

AU - Lu, Kuan Ying

AU - Yen, Tim Ting Chung

AU - Chang, Chien Wen

AU - Chan, Hong Lin

AU - Tao, Mi Hua

AU - Liou, Jun Yang

AU - Chang, Margaret Dah Tsyr

AU - Su, Ih Jen

AU - Wang, Lily Hui Ching

PY - 2018/8

Y1 - 2018/8

N2 - 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.

AB - 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.

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U2 - 10.1002/path.5102

DO - 10.1002/path.5102

M3 - Article

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VL - 245

SP - 502

EP - 513

JO - Journal of Pathology

JF - Journal of Pathology

SN - 0022-3417

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