Oxidative stress and hepatocarcinogenesis in hepatitis C

我们已经发现，丙型肝炎病毒（HCV）的核心蛋白诱导氧化DNA损伤，而它抑制细胞凋亡，伴随着活性氧产生的增强。HCV核心蛋白通过增加Bcl-xL蛋白和减少Bax蛋白来抑制细胞凋亡，从而抑制细胞色素c从线粒体释放到细胞质中。然而，由HCV核心蛋白本身诱导的氧化应激的大小似乎不足以促进肝细胞癌（HCC）的发生。因此，我们将重点放在丙型肝炎中观察到的肝脏铁过载作为放大氧化应激的第二次打击。我们建立了表达HCV多聚蛋白的转基因小鼠，其肝脏铁浓度与慢性丙型肝炎患者相当。这些小鼠表现出明显的肝脂肪变性，包括小叶中心微泡型，线粒体超微结构改变，脂肪酸降解活性降低，脂质过氧化产物和8-羟基-2 '-脱氧鸟苷含量增加。最后，这些小鼠中有45%发生了肝肿瘤，包括HCC。从这些结果，它已被证明，由HCV蛋白的氧化应激和细胞凋亡调节是相互独立的，铁过载诱导线粒体损伤和增加的风险HCC发展的转基因小鼠表达的HCV多蛋白。

We have found that hepatitis C virus (HCV) core protein induces oxidative DNA damage, whereas it inhibits apoptosis that is accompanied by enhancement of reactive oxygen species production. HCV core protein inhibited apoptosis by increasing Bcl-xL protein and decreasing Bax protein, resulting in suppression of cytochrome c release from mitochondria into cytoplasm. However, magnitude of oxidative stress induced by HCV core protein itself seemed to be not enough for the development of hepatocellular carcinoma (HCC). We, therefore, focused on hepatic iron overload observed in hepatitis C as a second hit for amplifying oxidative stress. We established transgenic mice expressing the HCV polyprotein whose hepatic iron concentrations was comparable to those of patients with chronic hepatitis C. These mice showed marked hepatic steatosis including the centrilobular microvesicular type, ultrastructural alternations of the mitochondria, decreased degradation activity of fatty acid, and increased hepatic content of lipid peroxidation products and 8-hydroxy-2'-deoxyguanosine. Finally liver tumors including HCC developed in 45% of these mice. From these results, it has been shown that oxidative stress and apoptosis modulation by HCV protein are independent of each other, and that iron overload induces mitochondrial injury and increases the risk of HCC development in transgenic mice expressing the HCV polyprotein.