Liu Jie, Ahiekpor Angela, Li Li, Li Xianxing, Arbuthnot Patrick, Kew Michael, Feitelson Mark A
Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA.
Int J Cancer. 2009 Oct 15;125(8):1894-901. doi: 10.1002/ijc.24580.
Hepatitis B x antigen, or HBxAg, contributes importantly to the pathogenesis of hepatocellular carcinoma (HCC). Given that HBxAg constitutively activates beta-catenin and that upregulated ErbB-2 promotes beta-catenin signaling in other tumor types, experiments were designed to ask whether HBxAg was associated with upregulated expression of ErbB-2. When HBxAg positive and negative HepG2 cells were subjected to proteomics analysis, ErbB-2 was shown to be upregulated in HepG2X but not control cells. ErbB-2 was also strongly upregulated in HB infected liver, and weakly in some HCC nodules, where it correlated with HBxAg expression. Among tumor bearing patients, strong ErbB-2 staining in the liver was associated with dysplasia, and a shorter survival after tumor diagnosis. This implies that elevated ErbB-2 is an early marker of HCC. Treatment of HepG2X cells with ErbB-2 specific siRNA not only reduced ErbB-2 expression, but also reduced the expression of beta-catenin, suggesting that ErbB-2 contributed to the stabilization of beta-catenin. ErbB-2 specific siRNA also partially blocked the ability of HBxAg to promote DNA synthesis and growth of HepG2 cells. These results suggest that ErbB-2/beta-catenin up-regulation contributes importantly to the mechanism of HBxAg mediated hepatocellular growth.
乙肝X抗原（HBxAg）在肝细胞癌（HCC）的发病机制中起着重要作用。鉴于HBxAg持续激活β-连环蛋白，且在其他肿瘤类型中上调的ErbB-2可促进β-连环蛋白信号传导，因此设计实验来探究HBxAg是否与ErbB-2表达上调有关。对HBxAg阳性和阴性的HepG2细胞进行蛋白质组学分析时，发现ErbB-2在HepG2X细胞中上调，而在对照细胞中未上调。在乙肝感染的肝脏中，ErbB-2也强烈上调，在一些肝癌结节中则轻度上调，且与HBxAg表达相关。在荷瘤患者中，肝脏中强烈的ErbB-2染色与发育异常相关，且肿瘤诊断后的生存期较短。这意味着ErbB-2升高是肝癌的早期标志物。用ErbB-2特异性小干扰RNA（siRNA）处理HepG2X细胞，不仅降低了ErbB-2的表达，还降低了β-连环蛋白的表达，表明ErbB-2有助于β-连环蛋白的稳定。ErbB-2特异性siRNA也部分阻断了HBxAg促进HepG2细胞DNA合成和生长的能力。这些结果表明，ErbB-2/β-连环蛋白上调在HBxAg介导的肝细胞生长机制中起着重要作用。
