Hepatic IFIT3 predicts interferon-alpha therapeutic response in patients of hepatocellular carcinoma.
(1) Yang Y (2) Zhou Y (3) Hou J (4) Bai C (5) Li Z (6) Fan J (7) Ng IO (8) Zhou W (9) Sun H (10) Dong Q (11) Lee JM (12) Lo CM (13) Man K (14) Yang Y (15) Li N (16) Ding G (17) Yu Y (18) Cao X
(1) Yang Y (2) Zhou Y (3) Hou J (4) Bai C (5) Li Z (6) Fan J (7) Ng IO (8) Zhou W (9) Sun H (10) Dong Q (11) Lee JM (12) Lo CM (13) Man K (14) Yang Y (15) Li N (16) Ding G (17) Yu Y (18) Cao X
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 HCC patients, therefore identifying biomarkers to predict the response to IFN-alpha therapy is of high significance and clinical utility. As the induced IFN-stimulated genes (ISGs) expression following IFN-alpha treatment plays pivotal roles in IFN-alpha effects, we screened ISGs expression in HCC tissues and found several ISGs were significantly decreased in HCC. Interestingly, expressions of IFN-induced proteins with tetratricopeptide repeats (IFIT) family members, including IFIT1, IFIT2, IFIT3, and IFIT5, were all decreased in HCC tissues. We further analyzed the expressions 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 hetero-dimerization 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. This article is protected by copyright. All rights reserved.
Author Info:
(1) Department of Oncology, Department of Internal Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, 100005, China. Department of Immun
ology & Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100005, China. Department of Organ Transplantation, Shanghai Changzheng Hospital, Shanghai, 200003, China. (2) National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai, 200433, China. (3) National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai, 200433, China. (4) Department of Oncology, Department of Internal Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, 100005, China. (5) National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai, 200433, China. (6) Liver Cancer Institute and Zhongshan Hospital, Institutes of Biomedical Science, Fudan University, Shanghai, 200032, China. (7) Departments of Pathology and Surgery, State Key Laboratory for Liver Research, University of Hong Kong, Hong Kong, 999077, China. (8) Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, 200438, China. (9) Liver Cancer Institute and Zhongshan Hospital, Institutes of Biomedical Science, Fudan University, Shanghai, 200032, China. (10) Liver Cancer Institute and Zhongshan Hospital, Institutes of Biomedical Science, Fudan University, Shanghai, 200032, China. (11) Departments of Pathology and Surgery, State Key Laboratory for Liver Research, University of Hong Kong, Hong Kong, 999077, China. (12) Departments of Pathology and Surgery, State Key Laboratory for Liver Research, University of Hong Kong, Hong Kong, 999077, China. (13) Departments of Pathology and Surgery, State Key Laboratory for Liver Research, University of Hong Kong, Hong Kong, 999077, China. (14) Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, 200438, China. (15) National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai, 200433, China. (16) Department of Organ Transplantation, Shanghai Changzheng Hospital, Shanghai, 200003, China. (17) National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai, 200433, China. (18) Department of Immunology & Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100005, China. National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai, 200433, China.
