國家衛生研究院 NHRI:Item 3990099045/9619
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    题名: Hepatitis B virus PreS2-mutant large surface antigen activates store-operated calcium entry and promotes chromosome instability
    作者: Yen, TT;Yang, A;Chiu, WT;Li, TN;Wang, LH;Wu, YH;Wang, HC;Chen, L;Wang, WC;Huang, W;Chang, CW;Chang, MD;Shen, MR;Su, IJ;Wang, LH
    贡献者: Division of Infectious Diseases
    摘要: 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.
    日期: 2016-04
    關聯: Oncotarget. 2016 Apr;7(17):23346-23360.
    Link to: http://dx.doi.org/10.18632/oncotarget.8109
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000377706200029
    Cited Times(Scopus): http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=84966605211
    显示于类别:[蘇益仁(2002-2015)] 期刊論文

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