Hepatitis B virus preS2-mutant large surface antigen activates store-operated calcium entry and promotes chromosome instability

Tim Ting Chung Yen, Anderson Yang, Wen Tai Chiu, Tian Neng Li, Lyu Han Wang, Yi Hsuan Wu, Hui Chen Wang, Linyi Chen, Wen Ching Wang, Wenya Huang, Chien Wen Chang, Margaret Dah Tsyr Chang, Meng Ru Shen, Ih Jen Su, Lily Hui Ching Wang

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Hepatitis B virus (HBV) is a driver of hepatocellular carcinoma, and two viral products, X and large surface antigen (LHBS), are viral oncoproteins. During chronic viral infection, immune-escape mutants on the preS2 region of LHBS (preS2-LHBS) are gain-of-function mutations that are linked to preneoplastic ground glass hepatocytes (GGHs) and early disease onset of hepatocellular carcinoma. Here, we show that preS2-LHBS provoked calcium release from the endoplasmic reticulum (ER) and triggered stored-operated calcium entry (SOCE). The activation of SOCE increased ER and plasma membrane (PM) connections, which was linked by ER-resident stromal interaction molecule-1 (STIM1) protein and PM-resident calcium release-activated calcium modulator 1 (Orai1). Persistent activation of SOCE induced centrosome overduplication, aberrant multipolar division, chromosome aneuploidy, anchorage-independent growth, and xenograft tumorigenesis in hepatocytes expressing preS2-LHBS. Chemical inhibitions of SOCE machinery and silencing of STIM1 significantly reduced centrosome numbers, multipolar division, and xenograft tumorigenesis induced by preS2-LHBS. These results provide the first mechanistic link between calcium homeostasis and chromosome instability in hepatocytes carrying preS2-LHBS. Therefore, persistent activation of SOCE represents a novel pathological mechanism in HBV-mediated hepatocarcinogenesis.

Original languageEnglish
Pages (from-to)23346-23360
Number of pages15
JournalOncotarget
Volume7
Issue number17
DOIs
Publication statusPublished - 2016 Apr 26

Fingerprint

Chromosomal Instability
Surface Antigens
Hepatitis B virus
Calcium
Endoplasmic Reticulum
Hepatocytes
Centrosome
Heterografts
Hepatocellular Carcinoma
Carcinogenesis
Cell Membrane
Oncogene Proteins
Aneuploidy
Virus Diseases
Glass
Homeostasis
Chromosomes
Mutation

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

Yen, Tim Ting Chung ; Yang, Anderson ; Chiu, Wen Tai ; Li, Tian Neng ; Wang, Lyu Han ; Wu, Yi Hsuan ; Wang, Hui Chen ; Chen, Linyi ; Wang, Wen Ching ; Huang, Wenya ; Chang, Chien Wen ; Chang, Margaret Dah Tsyr ; Shen, Meng Ru ; Su, Ih Jen ; Wang, Lily Hui Ching. / Hepatitis B virus preS2-mutant large surface antigen activates store-operated calcium entry and promotes chromosome instability. In: Oncotarget. 2016 ; Vol. 7, No. 17. pp. 23346-23360.
@article{8051c457f0644a4eaa6ec2b3bb8cbf28,
title = "Hepatitis B virus preS2-mutant large surface antigen activates store-operated calcium entry and promotes chromosome instability",
abstract = "Hepatitis B virus (HBV) is a driver of hepatocellular carcinoma, and two viral products, X and large surface antigen (LHBS), are viral oncoproteins. During chronic viral infection, immune-escape mutants on the preS2 region of LHBS (preS2-LHBS) are gain-of-function mutations that are linked to preneoplastic ground glass hepatocytes (GGHs) and early disease onset of hepatocellular carcinoma. Here, we show that preS2-LHBS provoked calcium release from the endoplasmic reticulum (ER) and triggered stored-operated calcium entry (SOCE). The activation of SOCE increased ER and plasma membrane (PM) connections, which was linked by ER-resident stromal interaction molecule-1 (STIM1) protein and PM-resident calcium release-activated calcium modulator 1 (Orai1). Persistent activation of SOCE induced centrosome overduplication, aberrant multipolar division, chromosome aneuploidy, anchorage-independent growth, and xenograft tumorigenesis in hepatocytes expressing preS2-LHBS. Chemical inhibitions of SOCE machinery and silencing of STIM1 significantly reduced centrosome numbers, multipolar division, and xenograft tumorigenesis induced by preS2-LHBS. These results provide the first mechanistic link between calcium homeostasis and chromosome instability in hepatocytes carrying preS2-LHBS. Therefore, persistent activation of SOCE represents a novel pathological mechanism in HBV-mediated hepatocarcinogenesis.",
author = "Yen, {Tim Ting Chung} and Anderson Yang and Chiu, {Wen Tai} and Li, {Tian Neng} and Wang, {Lyu Han} and Wu, {Yi Hsuan} and Wang, {Hui Chen} and Linyi Chen and Wang, {Wen Ching} and Wenya Huang and Chang, {Chien Wen} and Chang, {Margaret Dah Tsyr} and Shen, {Meng Ru} and Su, {Ih Jen} and Wang, {Lily Hui Ching}",
year = "2016",
month = "4",
day = "26",
doi = "10.18632/oncotarget.8109",
language = "English",
volume = "7",
pages = "23346--23360",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals",
number = "17",

}

Yen, TTC, Yang, A, Chiu, WT, Li, TN, Wang, LH, Wu, YH, Wang, HC, Chen, L, Wang, WC, Huang, W, Chang, CW, Chang, MDT, Shen, MR, Su, IJ & Wang, LHC 2016, 'Hepatitis B virus preS2-mutant large surface antigen activates store-operated calcium entry and promotes chromosome instability', Oncotarget, vol. 7, no. 17, pp. 23346-23360. https://doi.org/10.18632/oncotarget.8109

Hepatitis B virus preS2-mutant large surface antigen activates store-operated calcium entry and promotes chromosome instability. / Yen, Tim Ting Chung; Yang, Anderson; Chiu, Wen Tai; Li, Tian Neng; Wang, Lyu Han; Wu, Yi Hsuan; Wang, Hui Chen; Chen, Linyi; Wang, Wen Ching; Huang, Wenya; Chang, Chien Wen; Chang, Margaret Dah Tsyr; Shen, Meng Ru; Su, Ih Jen; Wang, Lily Hui Ching.

In: Oncotarget, Vol. 7, No. 17, 26.04.2016, p. 23346-23360.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Hepatitis B virus preS2-mutant large surface antigen activates store-operated calcium entry and promotes chromosome instability

AU - Yen, Tim Ting Chung

AU - Yang, Anderson

AU - Chiu, Wen Tai

AU - Li, Tian Neng

AU - Wang, Lyu Han

AU - Wu, Yi Hsuan

AU - Wang, Hui Chen

AU - Chen, Linyi

AU - Wang, Wen Ching

AU - Huang, Wenya

AU - Chang, Chien Wen

AU - Chang, Margaret Dah Tsyr

AU - Shen, Meng Ru

AU - Su, Ih Jen

AU - Wang, Lily Hui Ching

PY - 2016/4/26

Y1 - 2016/4/26

N2 - Hepatitis B virus (HBV) is a driver of hepatocellular carcinoma, and two viral products, X and large surface antigen (LHBS), are viral oncoproteins. During chronic viral infection, immune-escape mutants on the preS2 region of LHBS (preS2-LHBS) are gain-of-function mutations that are linked to preneoplastic ground glass hepatocytes (GGHs) and early disease onset of hepatocellular carcinoma. Here, we show that preS2-LHBS provoked calcium release from the endoplasmic reticulum (ER) and triggered stored-operated calcium entry (SOCE). The activation of SOCE increased ER and plasma membrane (PM) connections, which was linked by ER-resident stromal interaction molecule-1 (STIM1) protein and PM-resident calcium release-activated calcium modulator 1 (Orai1). Persistent activation of SOCE induced centrosome overduplication, aberrant multipolar division, chromosome aneuploidy, anchorage-independent growth, and xenograft tumorigenesis in hepatocytes expressing preS2-LHBS. Chemical inhibitions of SOCE machinery and silencing of STIM1 significantly reduced centrosome numbers, multipolar division, and xenograft tumorigenesis induced by preS2-LHBS. These results provide the first mechanistic link between calcium homeostasis and chromosome instability in hepatocytes carrying preS2-LHBS. Therefore, persistent activation of SOCE represents a novel pathological mechanism in HBV-mediated hepatocarcinogenesis.

AB - Hepatitis B virus (HBV) is a driver of hepatocellular carcinoma, and two viral products, X and large surface antigen (LHBS), are viral oncoproteins. During chronic viral infection, immune-escape mutants on the preS2 region of LHBS (preS2-LHBS) are gain-of-function mutations that are linked to preneoplastic ground glass hepatocytes (GGHs) and early disease onset of hepatocellular carcinoma. Here, we show that preS2-LHBS provoked calcium release from the endoplasmic reticulum (ER) and triggered stored-operated calcium entry (SOCE). The activation of SOCE increased ER and plasma membrane (PM) connections, which was linked by ER-resident stromal interaction molecule-1 (STIM1) protein and PM-resident calcium release-activated calcium modulator 1 (Orai1). Persistent activation of SOCE induced centrosome overduplication, aberrant multipolar division, chromosome aneuploidy, anchorage-independent growth, and xenograft tumorigenesis in hepatocytes expressing preS2-LHBS. Chemical inhibitions of SOCE machinery and silencing of STIM1 significantly reduced centrosome numbers, multipolar division, and xenograft tumorigenesis induced by preS2-LHBS. These results provide the first mechanistic link between calcium homeostasis and chromosome instability in hepatocytes carrying preS2-LHBS. Therefore, persistent activation of SOCE represents a novel pathological mechanism in HBV-mediated hepatocarcinogenesis.

UR - http://www.scopus.com/inward/record.url?scp=84966605211&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84966605211&partnerID=8YFLogxK

U2 - 10.18632/oncotarget.8109

DO - 10.18632/oncotarget.8109

M3 - Article

C2 - 26992221

AN - SCOPUS:84966605211

VL - 7

SP - 23346

EP - 23360

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 17

ER -