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Background and Purposes: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and is among the leading causes of cancerrelated death, especially in China.Systemic and targeted therapies, such as interferonalpha (IFN-α)therapy, may provide clinical benefit in prolonging patients survival,but the difficulty to identify patients who might respond well often makes these targeted adjuvant therapies less effective.For IFN-α, clinical trials have demonstrated its benefit in both the hematological and solid tumors, but it has been suggested to be effective in a subgroup of HCC patients.Thus, identification of molecular biomarkers that can identify HCC patients sensitive to IFN-α therapy would be very helpful in the clinic.Furthermore, HCC occurs mainly in men, which is the key and most interesting feature of HCC carcinogenesis.And the molecular mechanisms responsible for HCC gender disparity remain unclear.Methods: This study involved four independent cohorts of HCC patients.Cohort 1 and 2 included 152 and 140 HCC patients respectively, and RIG-I mRNA level was determined in these cohorts using qRT-PCR assay and the correlation of RIG-I expression with gender and survival was analyzed.Cohort 3 and 4 included 76 and 75 HCC patients respectively and they were from two independent, prospective, randomized, controlled trials of adjuvant IFN-α therapy for HCC patients.In Cohort 3 and 4, RIG-I protein level was determined using immunohistochemistry tissue microarray and its correlation with gender and survival was analyzed.And we also evaluated the association between RIG-I expression and response to IFN-α therapy in these patients.Furthermore, RIG-I expression in man and woman normal liver tissues was detected and the roles of RIG-I deficiency in DEN-induced HCC model were evaluated.Additionally, the molecular mechanisms responsible for RIG-I in promoting IFN-JAK-STAT pathway were further examined.Results: We used microArray analysis of gene expression in HCC tissues and matched nontumor liver tissues, and focused on the deregulated interferon-stimulated genes (ISGs) in HCC.We found that expression of RIG-I, one of the ISGs, was significantly downregulated in HCC tissues.And patients with low RIG-I expression had shorter survival and poorer response to interferon-αt therapy, suggesting that RIGI is a useful prognosis and interferon-α response predictor for HCC patients.Mechanistically, RIG-I enhances interferon-α response by amplifying interferon-αeffector signaling via strengthening STAT1 activation, and RIG-I strengthens STAT1 activation through disruption of SHP1-STAT1 interaction and STAT1 dephosphorylation.Furthermore, RIG-I deficiency promotes DEN-induced HCC carcinogenesis in mice, and hepatic RIG-I expression is lower in men than in women.Hence, RIG-I may contribute to HCC gender disparity of carcinogenesis.Conclusions: HCC patients with high RIG-I expression in tumor tissues responds better to adjuvant IFN-α therapy, and evaluating RIG-I expression in HCC tissues can identify the well-responders.RIG-I expression in the liver is higher in women than in men, and the differential hepatic RIG-I expression between genders may contribute to HCC gender disparity of carcinogenesis.