Institute for Biomedical Research, Xiamen University, Xiamen 361005, China.
FASEB J. 2011 Jan;25(1):192-205. doi: 10.1096/fj.10-166462. Epub 2010 Sep 16.
The orphan nuclear receptor Nur77 is an immediate-early response gene whose expression is rapidly induced by various extracellular stimuli. The aims of this study were to study the role of Nur77 expression in the growth and survival of colon cancer cells and the mechanism by which Nur77 expression was regulated. We showed that levels of Nur77 were elevated in a majority of human colon tumors (9/12) compared to their nontumorous tissues and that Nur77 expression could be strongly induced by different colonic carcinogens including deoxycholic acid (DCA). DCA-induced Nur77 expression resulted in up-regulation of antiapoptotic BRE and angiogenic VEGF, and it enhanced the growth, colony formation, and migration of colon cancer cells. In studying the mechanism by which Nur77 was regulated in colon cancer cells, we found that β-catenin was involved in induction of Nur77 expression through its activation of the transcriptional activity of AP-1 (c-Fos/c-Jun) that bound to and transactivated the Nur77 promoter. Together, our results demonstrate that Nur77 acts to promote the growth and survival of colon cancer cells and serves as an important mediator of the Wnt/β-catenin and AP-1 signaling pathways.
孤儿核受体 Nur77 是一种即刻早期反应基因，其表达可被各种细胞外刺激迅速诱导。本研究旨在探讨 Nur77 表达在结肠癌细胞生长和存活中的作用及其调控机制。我们发现，与非肿瘤组织相比，大多数人结肠癌组织（9/12）中 Nur77 水平升高，并且不同结直肠致癌物（包括脱氧胆酸（DCA））可强烈诱导 Nur77 表达。DCA 诱导的 Nur77 表达导致抗凋亡 BRE 和血管生成 VEGF 的上调，并增强结肠癌细胞的生长、集落形成和迁移。在研究结肠癌细胞中 Nur77 调控的机制时，我们发现β-catenin 通过激活 AP-1（c-Fos/c-Jun）的转录活性参与 Nur77 表达的诱导，AP-1 与 Nur77 启动子结合并反式激活其活性。总之，我们的结果表明，Nur77 促进结肠癌细胞的生长和存活，并作为 Wnt/β-catenin 和 AP-1 信号通路的重要介质。
