Adjuvant interferon-a (IFN-a) therapy is used to control certain types of cancer in clinics. For hepatocellular carcinoma (HCC), IFN-a therapy is effective in only a subgroup of patients; therefore, identifying biomarkers to predict the response to IFN-a therapy is of high significance and clinical utility. As the induced IFN-stimulated gene expression following IFN-a treatment plays pivotal roles in IFN-a effects, we screened IFN-stimulated gene expression in HCC tissues and found that several

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... IFN-stimulated genes were significantly decreased in HCC. Interestingly, expression of IFN-induced protein with tetratricopeptide repeats (IFIT) family members, including IFIT1, IFIT2, IFIT3, and IFIT5, was decreased in HCC tissues. We further analyzed the expression of IFIT family members in HCC and their roles in patients' responses to IFN-a therapy in two independent randomized controlled IFN-a therapy clinical trials of HCC patients. We found that higher expression of IFIT3, but not other IFITs, in HCC tissues predicts better response to IFN-a therapy, suggesting that IFIT3 may be a useful predictor of the response to IFN-a therapy in HCC patients. Mechanistically, IFIT3 enhanced the antitumor effects of IFN-a by promoting IFN-a effector responses both in vitro and in vivo. IFIT3 could bind signal transducer and activator of transcription 1 (STAT1) and STAT2 to enhance STAT1-STAT2 heterodimerization and nuclear translocation upon IFN-a treatment, thus promoting IFN-a effector signaling. Conclusion: Higher IFIT3 expression in HCC tissues predicts better response to IFN-a therapy in HCC patients; IFIT3 promotes IFN-a effector responses and therapeutic effects by strengthening IFN-a effector signaling in HCC. (HEPATOLOGY 2017;66:152-166)