Hepatitis B Virus Large Surface Antigen Promotes Liver Carcinogenesis by Activating the Src/PI3K/Akt Pathway
Hepatitis B Virus Large Surface Antigen Promotes Liver Carcinogenesis by Activating the Src/PI3K/Akt Pathway
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DOI：
10.1158/0008-5472.can-11-2260
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发表时间：
2011-12-15
期刊：
影响因子：
11.2
通讯作者：
Gu, Jianxin
中科院分区：
文献类型：
--
作者：
Liu, Haiou;Xu, Jiejie;Gu, Jianxin
由B型肝炎病毒（HBV）编码的三种包膜糖蛋白统称为HBV表面抗原（HBsAg），其中大的HBsAg（LHBs）糖蛋白在HBV相关的肝细胞癌中优先表达。LHB在转基因小鼠中可以作为癌基因，但它如何在功能上促进肝癌发生仍不清楚。在这项研究中，我们确定了乙肝病毒相关的肝癌发生过程中LHB的分子和功能作用。LHB增加肝癌细胞的肿瘤形成。此外，LHB的表达，而不是其他HBV包膜糖蛋白特异性地促进肝癌和肝细胞在体外的增殖。机制研究表明，这些作用是由LHB通过近端刺激PKC α/Raf 1信号传导激活Src/PI 3 K/Akt通路引起的。稳定的LHBs表达诱导的增殖与Src激酶激活介导的G（1）-S细胞周期进展和凋亡抵抗相关，如在肝细胞癌临床标本中所建立的。重要的是，通过施用Src抑制剂saracatinib逆转了LIFE诱导的细胞增殖和肿瘤形成。总之，我们的研究结果表明，LHB通过触发PKC α/Raf 1到Src/PI 3 K/Akt信号通路促进肝癌细胞的肿瘤发生，揭示了HBV相关肝癌发生的潜在机制的新见解。Cancer Res; 71（24）; 7547-57. (C)2011年AACR。
Of the three envelope glycoproteins encoded by hepatitis B virus (HBV) that are collectively referred to as HBV surface antigen (HBsAg), the large HBsAg (LHBs) glycoprotein is expressed preferentially in HBV-associated hepatocellular carcinoma. LHBs can act as an oncogene in transgenic mice, but how it contributes functionally to hepatocarcinogenesis remains unclear. In this study, we determined the molecular and functional roles of LHBs during HBV-associated hepatocarcinogenesis. LHBs increased tumor formation of hepatoma cells. Moreover, expression of LHBs but not other HBV envelope glycoproteins specifically promoted proliferation of hepatoma and hepatic cells in vitro. Mechanistic investigations revealed that these effects were caused by activation of the Src/PI3K/Akt pathway through proximal stimulation of PKC alpha/Raf1 signaling by LHBs. Proliferation induced by stable LHBs expression was associated with increased G(1)-S cell-cycle progression and apoptosis resistance mediated by Src kinase activation, as established in hepatocellular carcinoma clinical specimens. Importantly, LHBs-induced cellular proliferation and tumor formation were reversed by administration of the Src inhibitor saracatinib. Together, our findings suggest that LHBs promotes tumorigenesis of hepatoma cells by triggering a PKC alpha/Raf1 to Src/PI3K/Akt signaling pathway, revealing novel insights into the underlying mechanisms of HBV-associated hepatocarcinogenesis. Cancer Res; 71(24); 7547-57. (C) 2011 AACR.