All-trans retinoic acid induces XAF1 expression through an interferon regulatory factor-1 element in colon cancer
All-trans retinoic acid induces XAF1 expression through an interferon regulatory factor-1 element in colon cancer
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DOI：
10.1053/j.gastro.2005.12.017
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发表时间：
2006-03-01
期刊：
影响因子：
29.4
通讯作者：
Wong, BCY
中科院分区：
文献类型：
--
作者：
Wang, JD;Peng, Y;Wong, BCY
背景和目标：X连锁凋亡抑制蛋白（XIAP）相关因子：1（XAF 1）是一个新的肿瘤抑制和干扰素（IFN）刺激基因。全反式维甲酸（ATRA）通过上调干扰素调节因子1（IRF-1）及其下游干扰素刺激基因发挥抗肿瘤增殖作用。本研究旨在探讨全反式维甲酸对XAF 1表达的影响及其机制，以及XAF 1在其中的作用。ATRA诱导的结肠癌生长抑制方法：采用逆转录聚合酶链反应和免疫印迹技术检测基因表达。荧光素酶报告基因检测XAF 1启动子的转录活性。用电泳迁移率变动法和染色质免疫沉淀法测定IFN调节因子结合元件（IRF-E）的活性。通过在裸鼠异种移植物中的体外和体内评估细胞生长。结果：IFN-α剂量依赖性地刺激结肠癌细胞Lovo和SW 1116中XAF 1启动子活性。IRF-1结合元件（IRF-E-XAF 1）位于XAF 1基因ATG起始密码子上游的-30至-38核苷酸区域。IRF-E-XAF 1的定点突变消除了天然和IFN诱导的启动子活性和结合能力。ATRA通过与IRF-E-XAF 1相互作用在体外和体内诱导XAF 1表达。在体外和体内，XAF 1的过表达增加了细胞对ATRA诱导的生长抑制的易感性。此外，ATRA对XAF 1表达的影响与XIAP启动子甲基化和亚细胞分布无关。结论：XAF 1通过IRF 1介导的转录调控参与ATRA诱导的生长抑制。
Background & Aims: X-linked inhibitor of apoptosis protein (XIAP)-associated factor :1 (XAF1) is a novel tumor suppressor and interferon (IFN)-stimulated gene. All-trans retinoic acid (ATRA) exerts an anti proliferative effect on tumor cells through up-regulation of IFN regulatory factor 1 (IRF-1) and the downstream IFN-stimulated genes. The aim of this study was to determine the effect and mechanism of ATRA on XAF1 expression and the role of XAF1. in ATRA-Induced growth inhibition in colon cancer. Methods: Gene expression is detected by reverse-transcription polymerase chain reaction and immunoblotting. The transcription activity of XAF1 promoter is examined by luciferase reporter assay. The activity of IFN regulatory factor binding element (IRF-E) is assessed by electrophoretic mobility shift assay and chromatin immunoprecipitation assay. Cell growth is evaluated by both in vitro and in vivo in nude mice xenografts. Results: IFN-alfa stimulates XAF1 promoter activity in the colon cancer cells Lovo and SW1116 dose-dependently. An IRF-1 binding element (IRF-E-XAF1) is found in the -30 to -38 nucleotide region upstream of the ATG initiator codon of the XAF1 gene. Site-directed mutagenesis of IRF-E-XAF1 abrogates native and IFN-induced promoter activity and binding capacity. ATRA induces XAF1 expression both in vitro and in vivo through interaction with IRF-E-XAF1. Overexpression of XAF1 increases cell susceptibility to ATRA-induced growth suppression both in vitro and in vivo. Furthermore, the effect of ATRA on XAF1 expression is independent of the promoter methylation and the subcellular distribution of XIAP. Conclusions: XAF1 participates in ATRA-induced growth suppression through IRF1-mediated transcriptional regulation.