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Negative Feedback Regulation of IFN- Pathway by IFN Regulatory Factor 2 in Esophageal Cancers

¹ Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; ² College of Public Health, Zhengzhou University, Zhengzhou, China; ³ Department of Hematology and Oncology, Cedars-Sinai Medical Center, University of California at Los Angeles School of Medicine, Los Angeles, California; and ⁴ College of Life Sciences, Beijing University, Beijing, China

Requests for reprints: Dong Xie, Laboratory of Molecular Oncology, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 294 Tai-Yuan Road, Shanghai 200031, People's Republic of China. Phone: 86-21-54920918; Fax: 86-21-54920291; E-mail: dxie{at}sibs.ac.cn.

Key Words: ESCC • IFN- • IFNGR1 • IRF-1 • IRF-2

IFN- is an antitumor cytokine that inhibits cell proliferation and induces apoptosis after engagement with the IFN- receptors (IFNGR) expressed on target cells, whereas IFN regulatory factor 2 (IRF-2) is able to block the effects of IFN- by repressing transcription of IFN-–induced genes. Thus far, few studies have explored the influences of IFN- on human esophageal cancer cells. In the present study, therefore, we investigated in detail the functions of IFN- in esophageal cancer cells. The results in clinical samples of human esophageal cancers showed that the level of IFN- 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- 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-. Taken together, our results disclosed a new IRF-2–mediated inhibitory mechanism for IFN-–induced pathway in esophageal cancer cells: IFN- 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-. Accordingly, the results implied that IRF-2 might act as a mediator for the functions of IFN- and IFNGR1 in human esophageal cancers. [Cancer Res 2008;68(4):1136–43]