Department of Biomedicine and.
Carcinogenesis. 2014 Jan;35(1):114-22. doi: 10.1093/carcin/bgt258. Epub 2013 Jul 29.
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Most HCCs develop in cirrhotic livers. Alcoholic liver disease, chronic hepatitis B and chronic hepatitis C are the most common underlying liver diseases. Hepatitis C virus (HCV)-specific mechanisms that contribute to HCC are presently unknown. Transgenic expression of HCV proteins in the mouse liver induces an overexpression of the protein phosphatase 2A catalytic subunit (PP2Ac). We have previously reported that HCV-induced PP2Ac overexpression modulates histone methylation and acetylation and inhibits DNA damage repair. In this study, we analyze tumor formation and gene expression using HCV transgenic mice that overexpress PP2Ac and liver tissues from patients with HCC. We demonstrate that PP2Ac overexpression interferes with p53-induced apoptosis. Injection of the carcinogen, diethylnitrosamine, induced significantly more and larger liver tumors in HCV transgenic mice that overexpress PP2Ac compared with control mice. In human liver biopsies from patients with HCC, PP2Ac expression was significantly higher in HCC tissue compared with non-tumorous liver tissue from the same patients. Our findings demonstrate an important role of PP2Ac overexpression in liver carcinogenesis and provide insights into the molecular pathogenesis of HCV-induced HCC.
肝细胞癌 (HCC) 是全球最常见的癌症之一。大多数 HCC 发生在肝硬化肝脏中。酒精性肝病、慢性乙型肝炎和慢性丙型肝炎是最常见的潜在肝病。目前尚不清楚导致 HCC 的 HCV 特异性机制。HCV 蛋白在小鼠肝脏中的转基因表达会导致蛋白磷酸酶 2A 催化亚基 (PP2Ac) 的过度表达。我们之前曾报道过，HCV 诱导的 PP2Ac 过度表达会调节组蛋白甲基化和乙酰化，并抑制 DNA 损伤修复。在这项研究中，我们使用过度表达 PP2Ac 的 HCV 转基因小鼠和 HCC 患者的肝组织分析肿瘤形成和基因表达。我们证明 PP2Ac 过表达会干扰 p53 诱导的细胞凋亡。与对照小鼠相比，在用致癌剂二乙基亚硝胺注射后，过度表达 PP2Ac 的 HCV 转基因小鼠中诱导出的肝肿瘤数量更多、体积更大。在 HCC 患者的肝活检组织中，与同一患者的非肿瘤性肝组织相比，PP2Ac 的表达在 HCC 组织中明显更高。我们的研究结果表明 PP2Ac 过度表达在肝癌发生中起重要作用，并为 HCV 诱导的 HCC 的分子发病机制提供了新的见解。
