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, Wen-Ya Huang, Chien Wen Chang, Margaret Dah Tsyr Chang, Meng-Ru Shen, Ih Jen Su, Lily Hui Ching Wang

研究成果: Article

8 引文 (Scopus)

摘要

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.

原文English
頁(從 - 到)23346-23360
頁數15
期刊Oncotarget
7
發行號17
DOIs
出版狀態Published - 2016 四月 26

指紋

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

引用此文

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, Wen-Ya ; 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. 於: Oncotarget. 2016 ; 卷 7, 編號 17. 頁 23346-23360.
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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 Wen-Tai Chiu and Li, {Tian Neng} and Wang, {Lyu Han} and Wu, {Yi Hsuan} and Wang, {Hui Chen} and Linyi Chen and Wang, {Wen Ching} and Wen-Ya Huang and Chang, {Chien Wen} and Chang, {Margaret Dah Tsyr} and Meng-Ru Shen and Su, {Ih Jen} and Wang, {Lily Hui Ching}",
year = "2016",
month = "4",
day = "26",
doi = "10.18632/oncotarget.8109",
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Yen, TTC, Yang, A, Chiu, W-T, Li, TN, Wang, LH, Wu, YH, Wang, HC, Chen, L, Wang, WC, Huang, W-Y, Chang, CW, Chang, MDT, Shen, M-R, Su, IJ & Wang, LHC 2016, 'Hepatitis B virus preS2-mutant large surface antigen activates store-operated calcium entry and promotes chromosome instability', Oncotarget, 卷 7, 編號 17, 頁 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, Wen-Ya; Chang, Chien Wen; Chang, Margaret Dah Tsyr; Shen, Meng-Ru; Su, Ih Jen; Wang, Lily Hui Ching.

於: Oncotarget, 卷 7, 編號 17, 26.04.2016, p. 23346-23360.

研究成果: Article

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, Wen-Ya

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.

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