Suppression of IRF4 by IRF1, 3, and 7 in Noxa Expression Is a Necessary Event for IFN-γ-Mediated Tumor Elimination
Suppression of IRF4 by IRF1, 3, and 7 in Noxa Expression Is a Necessary Event for IFN-γ-Mediated Tumor Elimination
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DOI：
10.1158/1541-7786.mcr-11-0185
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发表时间：
2011-10-01
影响因子：
5.2
通讯作者：
Kim, Tae-Hyoung
中科院分区：
文献类型：
--
作者：
Piya, Sujan;Moon, Ae Ran;Kim, Tae-Hyoung
ifn - γ通过影响免疫细胞或肿瘤细胞在肿瘤免疫监视中发挥关键作用；然而，ifn介导的肿瘤消除作用在很大程度上是未知的。在这项研究中，我们发现IFN调节因子（IRF）通过IFN上调和下调各种癌细胞中Noxa（一种前体BH3蛋白）的表达。在肿瘤细胞中使用短发夹RNA抑制Noxa的表达导致对脂多糖（LPS）诱导的肿瘤消除的抵抗，其中ifn - γ被认为是小鼠的关键效应物。CT26细胞和SP2/0细胞分别对lps诱导的肿瘤消除敏感和抗性进行了染色质免疫沉淀分析，结果显示Noxa启动子区IRF1、3、4和7对ifn - γ的响应性可能在lps诱导的肿瘤消除中至关重要。ifn - γ上调IRF1、3和7，激活Noxa表达，导致Noxa野生型小鼠肾（BMK）细胞死亡，而Noxa缺乏的BMK细胞不死亡。相反，IRF4作为Noxa表达的抑制因子，抑制IRF1、3或7诱导的细胞死亡。因此，尽管ifn - γ在体外不能单独诱导肿瘤细胞死亡，但ifn - γ的Noxa诱导对于增加肿瘤细胞对免疫细胞介导的细胞毒性的易感性至关重要。ifn - γ受其激活因子（IRF1、3和7）和抑制因子（IRF4）之间的平衡调节。Mol - Cancer Res；9 (10);1356 - 65。(c) 2011年aacr。
IFN-gamma plays a critical role in tumor immunosurveillance by affecting either immune cells or tumor cells; however, IFN-mediated effects on tumor elimination are largely unknown. In this study, we showed that IFN regulatory factors (IRF) modulated by IFNs up- and downregulated Noxa expression, a prodeath BH3 protein, in various cancer cells. Inhibition of Noxa expression using short hairpin RNA in tumor cells leads to resistance against lipopolysaccharide (LPS)-induced tumor elimination, in which IFN-gamma is known as a critical effecter in mice. Chromatin immunoprecipitation analysis in both CT26 cells and SP2/0 cells, sensitive and resistant to LPS-induced tumor elimination, respectively, revealed that the responsiveness of IRF1, 3, 4, and 7 in the Noxa promoter region in response to IFN-gamma might be crucial in LPS-induced tumor elimination. IRF1, 3, and 7 were upregulated by IFN-gamma and activated Noxa expression, leading to the death of Noxa wild-type baby mouse kidney (BMK) cells but not of Noxa-deficient BMK cells. In contrast, IRF4 acts as a repressor for Noxa expression and inhibits cell death induced by IRF1, 3, or 7. Therefore, although IFN-gamma alone are not able to induce cell death in tumor cells in vitro, Noxa induction by IFN-gamma, which is regulated by the balance between its activators (IRF1, 3, and 7) and its repressor (IRF4), is crucial to increasing the susceptibility of tumor cells to immune cell-mediated cytotoxicity. Mol Cancer Res; 9(10); 1356-65. (C) 2011 AACR.