THE ROLES OF HEPATITIS C VIRUS AND INFLAMMATION IN THE PATHOGENESIS OF HEPATOCELLULAR CARCINOMA

丙型肝炎病毒（HCV）感染致肝癌的机制尚不明确。一种可能是与氧化应激有关，氧化应激可以产生基因突变和总体染色体改变，从而促进癌症的发展。我们最近的研究表明，HCV的核心蛋白在经过很长一段时间后，诱导肝脂肪变性明显但无炎症的转基因小鼠的肝细胞癌（HCC），这表明HCV直接参与肝癌的发生。16月龄以上老龄核心基因转基因小鼠PCOOH水平升高180%。同时，在同一小鼠中，过氧化氢酶活性显著增加，总谷胱甘肽和还原性谷胱甘肽水平降低。有趣的是，酒精引起转基因小鼠PCOOH水平显著升高，提示酒精和HCV在肝癌发生中有协同作用。因此，HCV核心蛋白在肝脏处于氧化/抗氧化状态后，在没有…更多的炎症，因此可能至少部分地促进或促进HCV感染中HCC的发展。由于先前的研究表明ROS与丝裂原活化蛋白激酶（MAPK）密切相关，我们在短期乙醇喂养的核心转基因和非转基因小鼠的肝脏中检测了c-Jun n-末端激酶、p38 MAPK和细胞外信号调节激酶（ERK）的活性。与非转基因小鼠相比，核心转基因小鼠的ERK和p38 MAPK活性增加，而正常饮食的核心转基因小鼠的ERK和p38 MAPK均未被激活。此外，环amp和血清反应元件（p38 MAPK和ERK的下游通路）的活性也增加。通过基因芯片和实时荧光定量PCR比较基因表达谱发现，与细胞转化相关的半乳糖凝集素-1在乙醇喂养的核心转基因小鼠中显著升高。另一方面，在细胞氧化应激保护中起关键作用的谷胱甘肽s -转移酶降低。综上所述，这些结果表明，HCV核心蛋白与乙醇合作激活了一些MAPK通路，并导致了一些基因的调节，从而导致了高乙醇消耗的HCV感染患者肝脏中的发病机制。少

The mechanism of hepatocarcinogenesis in hepatitis C virus (HCV) infection is still undefined. One possibility is the involvement of oxidative stress, which can produce genetic mutations as well as gross chromosomal alterations and contribute to cancer development. We recently showed that the core protein of HCV induces, after a long period, hepatocellular carcinoma (HCC) in transgenic mice with marked hepatic steatosis but without inflammation, indicating a direct involvement of HCV in hepatocarcinogenesis. PCOOH level was increased by 180% in old core gene transgenic mice aged over 16 months. Concurrently, there was a significant increase in the catalase activity, and decreases in the levels of total and reduced glutathione in the same mice. Interestingly, alcohol caused a marked increase in PCOOH level in transgenic mice, suggesting synergism between alcohol and HCV in hepatocarcinogenesis. The HCV core protein thus afters the oxidant/antioxidant state in the liver in the absence of … More inflammation, and thereby may contribute to or facilitate, at least partly, the development of HCC in HCV infection. Since previous studies indicated that ROS is closely associated with mitogen-activated protein kinases (MAPK), we examined activities of c-Jun N-terminal kinase, p38 MAPK, and extracellular signal-regulated kinase (ERK) in the liver of core-transgenic and nontransgenic mice with short-term ethanol feeding. Activity of ERK and p38 MAPK was increased in core-transgenic mice compared with nontransgenic mice, whereas neither ERK nor p38 MAPK was activated hi core-transgenic mice with normal diets. In addition, activity of cyclic-AMP and serum responsive element, downstream pathways of p38 MAPK and ERK, was also increased. Comparison of gene expression profiles by cDNA microarray and real-time PCR revealed that galectin-1, which is associated with cell transformation, was significantly increased in ethanol-fed core-transgenic mice. On the other hand, glutathione S-transferase, which plays a key role in protecting cells from oxidative stress, was decreased. In conclusion, these results suggest that HCV core protein cooperates with ethanol for the activation of some MAPK pathways, and leads to the modulation of several genes, contributing to pathogenesis observed in livers of HCV-infected patients with high ethanol consumption. Less