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.
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U2 - 10.18632/oncotarget.8109
DO - 10.18632/oncotarget.8109
M3 - Article
C2 - 26992221
AN - SCOPUS:84966605211
SN - 1949-2553
VL - 7
SP - 23346
EP - 23360
JO - Oncotarget
JF - Oncotarget
IS - 17
ER -