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Hepatitis B virus core protein promotes hepatocarcinogenesis by enhancing Src expression and activating the Src/PI3K/Akt pathway
Author(s) -
Liu Wei,
Guo Teng-Fei,
Jing Zhen-Tang,
Yang Zhi,
Liu Lei,
Yang Yuan-Ping,
Lin Xu,
Tong Qiao-Yun
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201701144r
Subject(s) - proto oncogene tyrosine protein kinase src , carcinogenesis , protein kinase b , hepatitis b virus , cancer research , pi3k/akt/mtor pathway , oncogene , kinase , chemistry , signal transduction , microbiology and biotechnology , biology , cell cycle , virus , virology , cell , gene , biochemistry
Hepatitis B virus core protein (HBc) is expressed preferentially in hepatitis B virus (HBV)–associated hepatocellular carcinoma (HCC). HBc can function as an oncogene arising from its gene regulatory properties, but how it contributes functionally to hepatocarcinogenesis remains unclear. In this study, we determined the molecular and functional roles of HBc during HBV‐associated hepatocellular tumorigenesis. HBc increased tumor formation of hepatoma cells. Moreover, expression of HBc specifically promoted proliferation of hepatoma cells in vitro. Mechanistic investigations revealed that these effects were caused by activation of the Src/PI3K/Akt pathway through proximal switch from inactive Src to the active form of the kinase by HBc. HBc‐mediated sarcoma (Src) kinase activation was associated with down‐regulation of C‐terminal Src kinase (Csk). In addition, HBc enhances Src expression by activation of alternative Src 1A promoter in an Sp1 transcription factor‐dependent manner. Proliferation induced by stable HBc expression was associated with increased G 1 −S cell cycle progression mediated by Src kinase activation. HBc‐induced cellular proliferation and tumor formation were reversed by administration of the Src inhibitor saracatinib. Together, our findings suggest that HBc promotes tumorigenesis of hepatoma cells by enhancing the expression of total Src and the active form of the kinase and subsequently activates Src/ PI3K/Akt signaling pathway, revealing novel insights into the underlying mechanisms of HBV‐associated hepatocarcinogenesis.—Liu W., Guo, T.‐F., Jing Z.‐T., Yang, Z., Liu, L., Yang, Y.‐P., Lin, X., Tong Q.‐Y. Hepatitis B virus core protein promotes hepatocarcinogenesis by enhancing Src expression and activating the Src/PI3K/Akt pathway. FASEB J. 32, 3033–3046 (2018). www.fasebj.org