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 journalArticlepeer-review

12 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

All Science Journal Classification (ASJC) codes

  • Oncology

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