Wang Yan, Liu Dong-Ping, Chen Ping-Ping, Koeffler H Phillip, Tong Xiang-Jun, Xie Dong
Laboratory of Molecular Oncology, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Cancer Res. 2007 Mar 15;67(6):2535-43. doi: 10.1158/0008-5472.CAN-06-3530.
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.
干扰素调节因子（IRF）-1和IRF-2通常分别被视为肿瘤抑制因子和癌蛋白。然而，它们在食管鳞状细胞癌（ESCC）中的表达和功能却鲜为人知。在我们目前的研究中，与配对的正常食管组织相比，ESCC中IRF-1表达降低而IRF-2表达增加。此外，统计数据表明IRF-2表达与ESCC的进展密切相关。正如预期的那样，在ESCC细胞系中过表达IRF-1或IRF-2分别导致细胞生长受到抑制或增强。而且，增殖和凋亡相关分子（p21（WAF1/CIP1）、细胞周期蛋白D1、Bcl-2和组蛋白H4）受IRF-1和IRF-2调控。此外，高水平的IRF-2通过阻止IRF-1转位到细胞核而阻断其功能；相反，用小干扰RNA敲低IRF-2可使IRF-1进入细胞核并发挥活性。使用裸鼠的体内实验表明，IRF-2过表达增强了ESCC细胞的致瘤性，但在强制表达IRF-1后显著减弱。总之，IRF-1和IRF-2能够分别作为抑癌蛋白和癌蛋白调节ESCC细胞的致瘤性。IRF-1与IRF-2的相对量对ESCC的发生和进展在功能上非常重要，IRF-1/IRF-2比值的降低可能导致ESCC细胞致瘤性增强。因此，IRF-1和IRF-2的水平是ESCC诊断和预后的有用指标，并且这些分子是ESCC治疗的潜在药物靶点。
