Interferon regulatory factor 8 functions as a tumor suppressor in renal cell carcinoma and its promoter methylation is associated with patient poor prognosis
Interferon regulatory factor 8 functions as a tumor suppressor in renal cell carcinoma and its promoter methylation is associated with patient poor prognosis
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干扰素调节因子 8 在肾细胞癌中发挥肿瘤抑制因子的作用，其启动子甲基化与患者不良预后相关
DOI：
10.1016/j.canlet.2014.07.040
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发表时间：
2014-11-28
期刊：
影响因子：
9.7
通讯作者：
Jin, Jie
中科院分区：
文献类型：
--
作者：
Zhang, Qian;Zhang, Lian;Jin, Jie
干扰素调节因子8（Interferon Regulatory Factor 8，IRF 8）作为IFN-γ信号传导的核心元件，在肿瘤抑制中起关键作用。然而，其在肾细胞癌（RCC）中的表达和潜在的分子机制仍不清楚。在此，我们检测了IRF 8在RCC细胞系和原发肿瘤中的表达和甲基化，并进一步评估了其肿瘤抑制功能。我们发现，IRF 8广泛表达于人类正常组织，包括肾脏，但经常下调启动子甲基化在RCC细胞系。在25%的原发肿瘤中检测到IRF 8甲基化，但在邻近的非恶性肾组织中未检测到，并且与RCC的较高肿瘤核分级相关。IRF 8的异位表达通过诱导细胞周期G2/M期阻滞和凋亡抑制肾癌细胞集落形成和迁移能力。IFN-γ可诱导肾癌细胞表达IRF 8，同时增加切割PARR。IRF 8可抑制癌基因YAP 1和Survivin的表达，上调抑癌基因CASP 1、p21和PTEN的表达。总的来说，我们的数据表明，IRF 8作为一种功能性肿瘤抑制因子在RCC中经常甲基化，IRF 8介导的干扰素信号参与RCC的发病机制。(C)2014爱思唯尔爱尔兰有限公司版权所有。
Interferon regulatory factor 8 (IRF8), as a central element of IFN-gamma-signaling, plays a critical role in tumor suppression. However, its expression and underlying molecular mechanism remain elusive in renal cell carcinoma (RCC). Here, we examined IRF8 expression and methylation in RCC cell lines and primary tumors, and further assessed its tumor suppressive functions. We found that IRF8 was widely expressed in human normal tissues including kidney, but frequently downregulated by promoter methylation in RCC cell lines. IRF8 methylation was detected in 25% of primary tumors, but not in adjacent non-malignant renal tissues, and associated with higher tumor nuclear grade of RCC. Ectopic expression of IRF8 inhibited colony formation and migration abilities of RCC cells, through inducing cell cycle G2/M arrest and apoptosis. IFN-gamma could induce IRF8 expression in RCC cells, together with increased cleaved-PARR We further found that IRF8 inhibited expression of oncogenes YAP1 and Survivin, as well as upregulated expression of tumor suppressor genes CASP1, p21 and PTEN. Collectively, our data demonstrate that IRF8 as a functional tumor suppressor is frequently methylated in RCC, and IRF8-mediated interferon signaling is involved in RCC pathogenesis. (C) 2014 Elsevier Ireland Ltd. All rights reserved.