Hepatitis C virus infection and mechanism of liver disease progression

摘要 丙型肝炎病毒(丙型肝炎病毒)经常导致持续感染，并是一个日益重要的因素 肝细胞癌的病因学。目前还没有预防或治疗性丙型肝炎疫苗 可用。直接抗病毒药物显著改善了丙型肝炎病毒感染的结局，尽管它没有 防止再次感染。此外，这种治疗费用高昂，而且已经面临新的问题，如病毒突变。 最近的研究表明，尽管治愈了，一些患者仍会进展为肝功能衰竭和/或癌症。 治疗后感染的可能性。因此，了解其潜在机制的研究迫在眉睫。 丙型肝炎病毒相关肝脏发病机制的研究。我们和其他人已经展示了转录调控活性 丙型肝炎病毒蛋白上的一些细胞基因，这可能形成恶性的遗传基础 感染肝细胞的转化。由于丙型肝炎最初会导致静止性疾病，我们不知道什么时候 受感染的细胞与病毒蛋白一起转化，以及参与者是谁。因此，我们在这笔赠款中的总体目标是 应用于阐明丙型肝炎介导的肝细胞癌的机制。我们观察到丙型肝炎 调节可影响肝细胞生长的microRNAs(MiRNA)。我们最近观察到丙型肝炎 原代人肝细胞感染促进上皮间充质细胞表型改变 转化(EMT)相关基因的表达，并产生肿瘤起始干细胞(TISCs)。基于 这一新信息，我们假设丙型肝炎调节miRNAs和信号通路 同时促进肝细胞生长，导致肝细胞癌进展。我们将验证我们的密钥 使用丙型肝炎感染患者的肝活检样本进行观察以保持人类的相关性。 研究抑制的基本步骤将为开发有效的治疗开辟新的途径 针对这种高度流行的疾病的战略。

Abstract Hepatitis C virus (HCV) often causes persistent infection, and is an increasingly important factor in the etiology of hepatocellular carcinoma (HCC). There is no preventive or therapeutic hepatitis C vaccine available. Direct antiviral agents have significantly improved outcome of HCV infection, although it does not prevent reinfection. Further, the treatment is costly and already faces new issues, such as viral mutation. Recent studies suggested that some patients still progress to liver failure and/or cancer despite being cured of infection after therapy. Therefore, studies are extremely urgent to understand the underlying mechanisms of HCV associated liver pathogenesis. We and others have shown transcriptional regulatory activities of hepatitis C proteins on a number of cellular genes, which may form the genetic basis for malignant transformation of infected hepatocytes. Since hepatitis C causes silent disease initially, we do not know when infected cells transform and who the players are along with viral proteins. Thus, our overall goal in this grant application is to delineate the mechanisms of hepatitis C mediated HCC. We observed that hepatitis C modulates microRNAs (miRNA) that can influence hepatocyte growth. We recently observed that hepatitis C infection of primary human hepatocytes induces phenotypic changes by enhancing epithelial mesenchymal transition (EMT) related gene expression, and generates tumor initiating stem-like cells (TISCs). Based on the novel information, we hypothesize that hepatitis C modulates miRNAs and signaling pathways concurrently to promote hepatocyte growth, leading to HCC progression. We will validate our key observations using liver biopsy specimens from hepatitis C infected patients to maintain human relevance. Examining essential steps for inhibition will open up new avenues for developing effective treatment strategies against this highly prevalent disease.