Negative feedback regulation of IFN-gamma pathway by IFN regulatory factor 2 in esophageal cancers.
IFN-gamma is an antitumor cytokine that inhibits cell proliferation and induces apoptosis after engagement with the IFN-gamma receptors (IFNGR) expressed on target cells, whereas IFN regulatory factor 2 (IRF-2) is able to block the effects of IFN-gamma by repressing transcription of IFN-gamma-induced genes. Thus far, few studies have explored the influences of IFN-gamma on human esophageal cancer cells. In the present study, therefore, we investigated in detail the functions of IFN-gamma in esophageal cancer cells. The results in clinical samples of human esophageal cancers showed that the level of IFN-gamma was increased in tumor tissues and positively correlated with tumor progression and IRF-2 expression, whereas the level of IFNGR1 was decreased and negatively correlated with tumor progression and IRF-2 expression. Consistently, in vitro experiments showed that low concentration of IFN-gamma induced the expression of IRF-2 with potential promotion of cell growth, and moreover, IRF-2 was able to suppress IFNGR1 transcription in human esophageal cancer cells by binding a specific motif in IFNGR1 promoter, which lowered the sensitivity of esophageal cancer cells to IFN-gamma. Taken together, our results disclosed a new IRF-2-mediated inhibitory mechanism for IFN-gamma-induced pathway in esophageal cancer cells: IFN-gamma induced IRF-2 up-regulation, then up-regulated IRF-2 decreased endogenous IFNGR1 level, and finally, the loss of IFNGR1 turned to enhance the resistance of esophageal cancer cells to IFN-gamma. Accordingly, the results implied that IRF-2 might act as a mediator for the functions of IFN-gamma and IFNGR1 in human esophageal cancers.
Wang
Yan
Y
Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Liu
Dongping
D
Chen
Pingping
P
Koeffler
H Phillip
HP
Tong
Xiangjun
X
Xie
Dong
D
D004938:Esophageal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005246:Feedback; D015870:Gene Expression; D006801:Humans; D050836:Interferon Regulatory Factor-2 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D017471:Receptors, Interferon / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D014158:Transcription, Genetic; D015854:Up-Regulation; D000096743:Interferon gamma Receptor
D050836:Interferon Regulatory Factor-2; D007371:Interferon-gamma; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor; C494229:IRF2 protein, human