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.

• Authors: 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
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 17 Pg. 23346-60 (Apr 26 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 26992221 (Publication Type: Journal Article)

Chemical References

• Calcium Channels
• Hepatitis B Surface Antigens
• Protein Precursors
• presurface protein 2, hepatitis B surface antigen
• Calcium

Topics

• Animals
• Calcium (metabolism)
• Calcium Channels (metabolism)
• Carcinoma, Hepatocellular (genetics, metabolism, virology)
• Cell Membrane (metabolism)
• Chromosomal Instability
• Endoplasmic Reticulum (metabolism)
• Hepatitis B (complications, genetics, virology)
• Hepatitis B Surface Antigens (genetics, metabolism)
• Hepatitis B virus (pathogenicity)
• Humans
• Liver Neoplasms (genetics, metabolism, virology)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Mutation
• Protein Precursors (genetics, metabolism)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays