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

丙型肝炎病毒（HCV）感染引起肝癌的机制尚不清楚。一种可能性是氧化应激的参与，它可以产生基因突变以及染色体的总体改变，并有助于癌症的发展。我们最近发现，丙型肝炎病毒的核心蛋白诱导，经过很长一段时间，肝细胞癌（HCC）的转基因小鼠有显着的肝脂肪变性，但没有炎症，表明直接参与丙型肝炎病毒在肝癌发生。在年龄超过16个月的老年核心基因转基因小鼠中，PCOH水平增加了180%。同时，在相同的小鼠中，过氧化氢酶活性显著增加，总谷胱甘肽和还原型谷胱甘肽水平降低。有趣的是，酒精引起转基因小鼠PCOH水平显着增加，表明酒精和HCV之间的协同作用，在肝癌发生。因此，HCV核心蛋白在肝脏中的氧化剂/抗氧化剂状态之后， ...更多信息 在HCV感染中，肝细胞癌的发生可能与炎症有关，从而可能至少部分地促成或促进HCC的发展。由于以往的研究表明，活性氧是密切相关的丝裂原活化蛋白激酶（MAPK），我们检查的c-Jun N-末端激酶，p38 MAPK，和细胞外信号调节激酶（ERK）在核心转基因和非转基因小鼠肝脏短期乙醇喂养的活动。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，而在正常饮食的核心转基因小鼠中ERK和p38 MAPK均未被激活。此外，p38 MAPK和ERK下游通路cyclic-AMP和血清反应元件的活性也增加。通过cDNA微阵列和实时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增加。另一方面，在保护细胞免受氧化应激中起关键作用的谷胱甘肽S-转移酶减少。总之，这些结果表明，HCV核心蛋白与乙醇合作激活一些MAPK途径，并导致几个基因的调制，有助于观察到的高酒精消耗的HCV感染患者的肝脏的发病机制。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