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Oncotarget. 2016 Apr 26;7(17):23346-60. doi: 10.18632/oncotarget.8109.

Hepatitis B virus PreS2-mutant large surface antigen activates store-operated calcium entry and promotes chromosome instability.

Author information

1
Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu 300, Taiwan.
2
Department of Biomedical Engineering, National Cheng Kung University, Tainan 701, Taiwan.
3
Center of Infectious Diseases and Signal Transduction, National Cheng Kung University, Tainan 701, Taiwan.
4
Institute of Pharmaceutics, Development Center for Biotechnology, Taipei 22180, Taiwan.
5
Institute of Molecular Medicine, National Tsing Hua University, Hsinchu 300, Taiwan.
6
Department of Medical Science, National Tsing Hua University, Hsinchu 300, Taiwan.
7
Department of Medical Laboratory Science and Biotechnology, National Cheng Kung University, Tainan 701, Taiwan.
8
Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu 300, Taiwan.
9
Department of Pharmacology, National Cheng Kung University, Tainan 701, Taiwan.
10
National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Tainan 704, Taiwan.
11
Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan 710, Taiwan.

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.

KEYWORDS:

ER stress; SOCE; aneuploidy; ground-glass hepatocytes; hepatitis B virus

PMID:
26992221
PMCID:
PMC5029631
DOI:
10.18632/oncotarget.8109
[Indexed for MEDLINE]
Free PMC Article

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