BACKGROUND: Hepatitis C virus (HCV) induces chronic liver diseases such as chronic hepatitis, cirrhosis, and eventually hepatocellular carcinoma (HCC). Either molecular or clinical studies support a correlation between HCV infection and insulin resistance. Patients with chronic HCV infection have a significantly increased prevalence of type 2 diabetes mellitus compared to controls or HBV-infected patients. The HCV core protein is known to contribute to insulin resistance related steatosis, fibrosis, and carcinogenesis of the liver. Although several hypotheses have been demonstrated, a mechanism of insulin resistance by HCV infection is complex and still unclear. AIM: The aim of this study is to investigate the molecular mechanisms of liver injury by HCV through insulin signaling pathway. MATERIALS AND METHODS: HCV infected cultured cells and transgenic mice expressing HCV core gene were used for this study. A HCV strain JFH-1 replicates efficiently in cultured cells with production of infectious HCV. A transgenic mouse was established by introducing the core gene derived from the HCV genome of genotype 1b. Total RNA was extracted from the cells with and without HCV infection, and the livers of transgenic mice and their littermate wild type mice. The cDNA was synthesized from the RNA then applied to the real-time PCR. The relative amount of the mRNAs of 84 genes related to the insulin receptor and target genes for insulin signaling were compared between the cells or tissues with or without HCV. RESULTS and DISCUSSION: The expression of one of the insulin receptor substrate (IRS) family mRNA was increased in cells infecting HCV, compared to uninfected cells. On the other hand, the Akt mRNA expressed at higher level in the liver of transgenic mouse than that of normal littermate. The IRS family proteins are key mediators in insulin signaling and have been reported to associate with glucose metabolism. The Akt protein kinase is a critical regulator of human physiology that controls an impressive array of diverse cellular functions, including the modulation of growth, survival, proliferation and metabolism. The activation of Akt signaling may induce not only the insulin resistance but also the development of HCCs in the patients with HCV chronic infection. CONCLUSIONS: Our results indicates that the alteration of IRS family and Akt expression by HCV could be predictive for insulin resistance. Since the insulin resistance promotes inflammation and fibrogenesis in the liver, HCV infection leads to the development of liver cirrhosis and HCC by activation of insulin signaling.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5100.

©2010 American Association for Cancer Research
2010