The orphan receptor TR3 suppresses intestinal tumorigenesis in mice by downregulating Wnt signalling
- Hang-Zi Chen1,
- Qing-Feng Liu1,
- Li Li1,
- Wei-Jia Wang1,
- Lu-Ming Yao1,
- Meng Yang1,
- Bo Liu1,
- Wei Chen1,
- Yan-Yan Zhan1,
- Ming-Qing Zhang2,
- Jian-Chun Cai3,
- Zhong-hui Zheng1,
- Sheng-Cai Lin1,
- Bo-An Li1,
- Qiao Wu1
- 1State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
- 2Southeast Hospital, Xiamen University, Zhangzhou, Fujian, China
- 3The First Affiliated Hospital of Xiamen University, Xiamen, Fujian, China
- Correspondence to Dr Qiao Wu and Dr Bo-an Li, State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China; ;
Contributors Conception and design, or analysis and interpretation of data: CHZ, LQF, LL, WWJ, YLM, YM, LB, CW, ZYY, ZMQ, CJC, ZZH, LBA, WQ. Drafting the article or revising it critically for important intellectual content: CHZ, LSC, LBA, WQ. Final approval of the version to be published: CHZ, LBA, WQ.
- Revised 9 July 2011
- Accepted 12 July 2011
- Published Online First 28 August 2011
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 Apcmin/+, Apcmin/+/TR3−/− and Apcmin/+/villin-TR3 mice. Wnt signalling activity was evaluated by assessing β-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 β-catenin/TCF4 was analysed by molecular methods in colorectal cancer cells. The phosphorylation of TR3 by glycogen synthase kinase (GSK) 3β and the correlation between GSK3β 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. Apcmin/+/TR3−/− mice developed more intestinal polyps than Apcmin/+/TR3+/+ mice, whereas either transgenic overexpression of TR3 in the intestine or treatment with cytosporone B in Apcmin/+ mice significantly decreased intestinal tumour number. Mechanistically, TR3 disrupted the association of β-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 GSK3β 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 Apcmin/+ mice. This inhibitory effect of TR3 may be paradoxically overcome through phosphorylation by GSK3β in clinical colorectal cancers.
- Wnt signalling
- intestinal tumorigenesis
- cell biology
- cell death
- cell growth
- cell proliferation
HZC, QFL and LL contributed equally to this work.
Funding This work was supported by grants from the National Natural Science Fund of China (30630070, 30810103905, 30971525, 30871281, 30871279, 90919037, 30921005); the ‘973’ Project of the Ministry of Science & Technology in China (2007CB914402, 2009CB52220); The National Key New Drug Creation Program of China (2009ZX09103-083) and the Science Planning Program of Fujian Province grant 2009J1010.
Competing interests None.
Provenance and peer review Commissioned; externally peer reviewed.