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	The orphan receptor TR3 suppresses intestinal tumorigenesis in mice by downregulating Wnt signalling
	Chen, Hang-Zi ; Liu, Qing-Feng ; Li, Li ; Wang, Wei-Jia ; Yao, Lu-Ming ; Yang, Meng ; Liu, Bo ; Chen, Wei ; Zhan, Yan-Yan ; Zhang, Ming-Qing ; Cai, Jian-Chun ; Zheng, Zhong-Hui ; Zheng ZH(郑忠辉) ; Lin, Sheng-Cai ; Lin SC(林圣彩) ; Li, Bo-An ; Wu, Qiao ; Wu Q(吴乔)
	2012-04
关键词	COLON-CARCINOMA CELLS BETA-CATENIN CANCER-CELLS COLORECTAL-CANCER ANDROGEN RECEPTOR NUCLEAR RECEPTORS CROSS-REGULATION NUR77 APOPTOSIS PATHWAYS
英文摘要	Aims Wnt signalling is involved in cellular homeostasis and development. Dysregulation of the Wnt signalling pathway has been linked to colorectal cancer. The orphan nuclear receptor TR3 plays important roles in proliferation and apoptosis. In this study, we investigated how TR3 suppresses intestinal tumorigenesis by regulating Wnt signalling. Methods Intestinal polyps were quantified in Apc(min/+), Apc(min/+)/TR3(-/-) and Apc(min/+)/villin-TR3 mice. Wnt signalling activity was evaluated by assessing beta-galactosidase activity in a BAT-Gal reporter strain. The TR3 agonist cytosporone B was used to evaluate the role of TR3 in intestinal tumorigenesis. Crosstalk between TR3 and beta-catenin/TCF4 was analysed by molecular methods in colorectal cancer cells. The phosphorylation of TR3 by glycogen synthase kinase (GSK) 3 beta and the correlation between GSK3 beta activity and TR3 phosphorylation were evaluated in clinical samples and colorectal cancer cells. Results TR3 was found to significantly suppress Wnt signalling activity and the proliferation of intestinal epithelial cells. Apc(min/+)/TR3(-/-) mice developed more intestinal polyps than Apc(min/+)/TR3(+/+) mice, whereas either transgenic overexpression of TR3 in the intestine or treatment with cytosporone B in Apc(min/+) mice significantly decreased intestinal tumour number. Mechanistically, TR3 disrupted the association of beta-catenin and TCF4 on chromatin and facilitated the recruitment of transcriptional co-repressors to the promoters of Wnt signalling target genes. However, TR3 was phosphorylated by GSK3 beta in most clinical colorectal cancers, which attenuated the inhibitory activity of TR3 towards Wnt signalling. Conclusions TR3 is a negative regulator of Wnt signalling and thus significantly suppresses intestinal tumorigenesis in Apc(min/+) mice. This inhibitory effect of TR3 may be paradoxically overcome through phosphorylation by GSK3 beta in clinical colorectal cancers.; National Natural Science Fund of China [30630070, 30810103905, 30971525, 30871281, 30871279, 90919037, 30921005]; Ministry of Science & Technology in China [2007CB914402, 2009CB52220]; The National Key New Drug Creation Program of China [2009ZX09103-083]; Science Planning Program of Fujian Province [2009J1010]
语种	英语
出版者	B M J PUBLISHING GROUP
内容类型	期刊论文
源URL	[http://dx.doi.org/10.1136/gutjnl-2011-300783]
专题	生命科学－已发表论文
推荐引用方式 GB/T 7714	Chen, Hang-Zi,Liu, Qing-Feng,Li, Li,et al. The orphan receptor TR3 suppresses intestinal tumorigenesis in mice by downregulating Wnt signalling[J],2012.
APA	Chen, Hang-Zi.,Liu, Qing-Feng.,Li, Li.,Wang, Wei-Jia.,Yao, Lu-Ming.,...&吴乔.(2012).The orphan receptor TR3 suppresses intestinal tumorigenesis in mice by downregulating Wnt signalling..
MLA	Chen, Hang-Zi,et al."The orphan receptor TR3 suppresses intestinal tumorigenesis in mice by downregulating Wnt signalling".(2012).

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