Hepatitis B virus PreS2-mutant large surface antigen activates store-operated calcium entry and promotes chromosome instability
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Tim Ting-Chung Yen1, Anderson Yang1, Wen-Tai Chiu2,3, Tian-Neng Li1, Lyu-Han Wang1, Yi-Hsuan Wu1, Hui-Chen Wang4, Linyi Chen5,6, Wen-Ching Wang1, Wenya Huang7, Chien-Wen Chang8, Margaret Dah-Tsyr Chang1,6, Meng-Ru Shen3,9, Ih-Jen Su3,10,11, Lily Hui-Ching Wang1,6
1Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu 300, Taiwan
2Department of Biomedical Engineering, National Cheng Kung University, Tainan 701, Taiwan
3Center of Infectious Diseases and Signal Transduction, National Cheng Kung University, Tainan 701, Taiwan
4Institute of Pharmaceutics, Development Center for Biotechnology, Taipei 22180, Taiwan
5Institute of Molecular Medicine, National Tsing Hua University, Hsinchu 300, Taiwan
6Department of Medical Science, National Tsing Hua University, Hsinchu 300, Taiwan
7Department of Medical Laboratory Science and Biotechnology, National Cheng Kung University, Tainan 701, Taiwan
8Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu 300, Taiwan
9Department of Pharmacology, National Cheng Kung University, Tainan 701, Taiwan
10National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Tainan 704, Taiwan
11Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan 710, Taiwan
Lily Hui-Ching Wang, e-mail: firstname.lastname@example.org
Ih-Jen Su, e-mail: email@example.com
Keywords: SOCE, ER stress, hepatitis B virus, ground-glass hepatocytes, aneuploidy
Received: August 21, 2015 Accepted: February 28, 2016 Published: March 16, 2016
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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