Hepatic IFIT3 Predicts Interferon-α Therapeutic Response in Patients of Hepatocellular Carcinoma

Adjuvant interferon-alpha (IFN-alpha) therapy is used to control certain types of cancer in clinics. For hepatocellular carcinoma (HCC), IFN-alpha therapy is effective in only a subgroup of patients; therefore, identifying biomarkers to predict the response to IFN-alpha therapy is of high significance and clinical utility. As the induced IFN-stimulated gene expression following IFN-alpha treatment plays pivotal roles in IFN-alpha effects, we screened IFN-stimulated gene expression in HCC tissues and found that several 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-alpha therapy in two independent randomized controlled IFN-alpha 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-alpha therapy, suggesting that IFIT3 may be a useful predictor of the response to IFN-alpha therapy in HCC patients. Mechanistically, IFIT3 enhanced the antitumor effects of IFN-alpha by promoting IFN-alpha 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-alpha treatment, thus promoting IFN-alpha effector signaling. Conclusion: Higher IFIT3 expression in HCC tissues predicts better response to IFN-alpha therapy in HCC patients; IFIT3 promotes IFN-alpha effector responses and therapeutic effects by strengthening IFN-alpha effector signaling in HCC.