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Involvement of IFN Regulatory Factor (IRF)-1 and IRF-2 in the Formation and Progression of Human Esophageal Cancers

¹ Laboratory of Molecular Oncology, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate School of the 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, Peking 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, China. Phone: 86-21-5492-0918; Fax: 86-21-5492-0291; E-mail: dxie{at}sibs.ac.cn.

IFN regulatory factor (IRF)-1 and IRF-2 are generally regarded as a tumor suppressor and an oncoprotein, respectively. However, little is known about their expression and function in esophageal squamous cell carcinomas (ESCC). In our present work, IRF-1 expression was decreased and IRF-2 expression was increased in ESCCs compared with matched normal esophageal tissues. Moreover, statistical data indicated that IRF-2 expression was tightly correlated with progression of ESCCs. As expected, overexpression of either IRF-1 or IRF-2 in an ESCC cell line resulted in either suppression or enhancement of cell growth, respectively. Also, proliferation- and apoptosis-related molecules (p21^WAF1/CIP1, cyclin-D1, Bcl-2, and histone H4) were regulated by IRF-1 and IRF-2. Additionally, high levels of IRF-2 blocked the function of IRF-1 by preventing the latter from translocating into the nucleus; in contrast, knock down of IRF-2 by small interfering RNA permitted nuclear localization and activity of IRF-1. In vivo assay using nude mice indicated that the tumorigenicity of ESCC cells was enhanced with IRF-2 overexpression but dramatically attenuated after forced expression of IRF-1. In conclusion, IRF-1 and IRF-2 are able to regulate tumorigenicity of ESCC cells as antioncoprotein and oncoprotein, respectively. Relative amounts of IRF-1 to IRF-2 are functionally very important for the development and progression of ESCCs, and reduction of the ratio of IRF-1/IRF-2 may lead to the enhancement of tumorigenicity of ESCC cells. Therefore, levels of IRF-1 and IRF-2 are useful indicators in diagnosis and prognosis for ESCCs, and these molecules are potential drug targets for ESCC therapy. [Cancer Res 2007;67(6):2535–43]

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