Hepatic IFIT3 Predicts Interferon-α Therapeutic Response in Patients of Hepatocellular Carcinoma
Hepatic IFIT3 Predicts Interferon-α Therapeutic Response in Patients of Hepatocellular Carcinoma
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肝脏 IFIT3 预测肝细胞癌患者的干扰素 α 治疗反应。
DOI：
10.1002/hep.29156
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发表时间：
2017-07-01
期刊：
影响因子：
13.5
通讯作者：
Cao, Xuetao
中科院分区：
文献类型：
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作者：
Yang, Yingyun;Zhou, Ye;Cao, Xuetao
辅助干扰素- α (ifn - α)治疗在临床上用于控制某些类型的癌症。对于肝细胞癌（HCC）， ifn - α治疗仅对一小部分患者有效；因此，识别生物标志物来预测对ifn - α治疗的反应具有很高的意义和临床实用性。由于ifn - α治疗后诱导的ifn刺激基因表达在ifn - α效应中起着关键作用，我们筛选了HCC组织中ifn刺激基因的表达，发现多个ifn刺激基因在HCC中显著降低。有趣的是，ifn诱导的四肽重复（IFIT）家族成员（包括IFIT1、IFIT2、IFIT3和IFIT5）蛋白在HCC组织中的表达降低。我们进一步分析了IFIT家族成员在HCC中的表达，并在两项独立的随机对照ifn - α治疗HCC患者临床试验中分析了IFIT家族成员在患者对ifn - α治疗反应中的作用。我们发现，HCC组织中IFIT3的高表达，而不是其他IFITs，预示着对ifn - α治疗的更好反应，这表明IFIT3可能是HCC患者对ifn - α治疗反应的有用预测因子。在机制上，IFIT3通过在体内和体外促进ifn - α效应反应来增强ifn - α的抗肿瘤作用。IFIT3可以结合信号换能器和转录激活器1 （STAT1）和STAT2，在ifn - α处理下增强STAT1-STAT2异源二聚化和核易位，从而促进ifn - α效应信号转导。结论：IFIT3在HCC组织中的高表达预示着肝癌患者对ifn - α治疗的更好反应；IFIT3通过加强肝癌中ifn - α效应信号传导，促进ifn - α效应反应和治疗效果。
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.