Pathogenesis of chronic hepatitis C and hepatocellular carcinoma and predictive factors determined by data mining

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BACKGROUND: Mechanisms involving resistance to interferon (IFN) and ribavirin (RBV) have wit been fully elucidated, and prediction of treatment responses before initiation of therapy is difficult. RIG-I and the related MDA5 initiate the host antiviral response by detecting intracellular viral dsRNA. Cardif (ISP-I, MAVS, VISA) is an adaptor molecule that connects RIG-I sensing to downstream signaling. On the other hand, LGP2, a helicase belonging RIG-I family, and an E3 ubiquitin ligase have been shown to negatively regulate RIG-I sensing. Moreover, these molecules are ISGylated by ISG15, a ubiquitin-like protein However; the clinical significance of these innate immune systems in terms of treatment response is unclear.AIM: To elucidate the mechanisms underlying resistance to PEG-IFN plus RBV, and to determine whether analysis of the innate immune system is useful in predicting treatment responses.METHODS: We studied 74 chronic hepatitis C virus (HCV) patients with genotype lb treated w … More ith PEG-IFN alfa-2b plus RBV for 48 weeks and 5 patients with non-viral liver disease. Pretreatment hepatic mRNA expressions of RIG-I, Cardif MDA5, LGP2, ISG15, USP18 (a specific remover of ISMS from ISGylated protein), and serum HCV dynamics during therapy were measured by real-time PCR. G3PDH and HMB were used as internal controls.RESULTS: Thirty-four patients were sustained virological responders (SVR), 24 were transient responders (TR), and 20 were non-virological responders (NVR). The hepatic levels of all transcripts except Cardif were 2. to 8-fold higher in HCV patients than non-HCV patients. RIG-I, MDA5, and LGP2 expression was significantly up-regulated in NVR compared with TR or SVR. Cardif expression negatively correlated with RIG-I expression and was significantly suppressed in NVR. The difference between NVR and SVR or TR in the RIG-I/Cardif expression ratio was pronounced (NVR/PR/SVR = 1.2/0.6/0.5 copies/control). Like RIG-I and MDA5, ISG15 and USP18 expression was significantly up-regulated in NVR (ISG15, NVR/TR/SVR = 0.8/0.4/0.2 copies/control; USP18, NVRTR/SVR = 0.9/0.6/0.4 copies/control). The RIG-I/Cardif ratio and the expression of MDA5, ISG15, and USP18 significantly correlated with viral decline rates in the first and second phases of HCV dynamics. Multivariate and ROC analyses revealed that a higher ratio of RIG-I/Cardif and a higher expression of MDA5, ISG15, and USP18 predicted NW.CONCLUSION: Intracellular sensors and their regulators were variously up-regulated upon HCV infection especially in NVR Quantifying hepatic gene expression involving an innate immune system is of use in identifying patients who are at a higher risk for NVR. Less