The orphan receptor TR3 suppresses intestinal tumorigenesis in mice by downregulating Wnt signalling.

Abstract

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 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. 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 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 Apc(min/+) mice. This inhibitory effect of TR3 may be paradoxically overcome through phosphorylation by GSK3β in clinical colorectal cancers.

• Authors: Hang-Zi Chen, Qing-Feng Liu, Li Li, Wei-Jia Wang, Lu-Ming Yao, Meng Yang, Bo Liu, Wei Chen, Yan-Yan Zhan, Ming-Qing Zhang, Jian-Chun Cai, Zhong-hui Zheng, Sheng-Cai Lin, Bo-An Li, Qiao Wu
• Journal: Gut (Gut) Vol. 61 Issue 5 Pg. 714-24 (May 2012) ISSN: 1468-3288 [Electronic] England
• PMID: 21873734 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
• Biomarkers, Tumor
• CTNNB1 protein, mouse
• Nr4a1 protein, mouse
• Nuclear Receptor Subfamily 4, Group A, Member 1
• Tcf4 protein, mouse
• Transcription Factor 4
• beta Catenin
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, mouse
• Glycogen Synthase Kinase 3
• beta-Galactosidase

Topics

• Animals
• Basic Helix-Loop-Helix Leucine Zipper Transcription Factors (metabolism)
• Biomarkers, Tumor (metabolism)
• Cell Proliferation
• Cell Transformation, Neoplastic (metabolism)
• Colorectal Neoplasms (metabolism, pathology)
• Down-Regulation
• Glycogen Synthase Kinase 3 (metabolism)
• Glycogen Synthase Kinase 3 beta
• Intestinal Mucosa (metabolism, pathology)
• Intestinal Polyps (metabolism, pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Nuclear Receptor Subfamily 4, Group A, Member 1 (metabolism)
• Phosphorylation
• Transcription Factor 4
• Wnt Signaling Pathway
• beta Catenin (metabolism)
• beta-Galactosidase (metabolism)