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Cooperation between the thyroid hormone receptor TRalpha1 and the WNT pathway in the induction of intestinal tumorigenesis.
- Source :
-
Gastroenterology [Gastroenterology] 2010 May; Vol. 138 (5), pp. 1863-74. Date of Electronic Publication: 2010 Jan 28. - Publication Year :
- 2010
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Abstract
- Background & Aims: Colorectal tumorigenesis is a multistep process involving the alteration of oncogenes and tumor suppressor genes, leading to the deregulation of molecular pathways that govern intestinal homeostasis. We have previously shown that the thyroid hormone receptor alpha1 (TRalpha1) controls intestinal development and homeostasis through the WNT pathway. More precisely, TRalpha1 directly enhances the transcription of several components of this pathway, allowing increased expression of beta-catenin/Tcf4 target genes and stimulation of cell proliferation. Because the WNT pathway is a major player in controlling intestinal homeostasis, we addressed whether the TRalpha1 receptor has tumor-inducing potential.<br />Methods: We generated mice overexpressing TRalpha1 specifically in the intestinal epithelium in a wild-type (vil-TRalpha1) or a WNT-activated (vil-TRalpha1/Apc(+/1638N)) genetic background.<br />Results: The intestine of vil-TRalpha1 mice presents aberrant intestinal mucosal architecture and increased cell proliferation and develops adenoma at a low rate. However, TRalpha1 overexpression is unable to induce cancer development. On the contrary, we observed accelerated tumorigenesis in vil-TRalpha1/Apc(+/1638N) mice compared with the Apc(+/1638N) mutants.<br />Conclusion: Our results suggest that this phenotype is due to cooperation between the activated TRalpha1 and WNT pathways. This is the first report describing the tumor-inducing function of TRalpha1 in the intestine.<br /> (Copyright 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Adenoma genetics
Adenoma pathology
Animals
Cell Proliferation
Cell Transformation, Neoplastic genetics
Cell Transformation, Neoplastic pathology
Disease Models, Animal
Gene Expression Regulation, Neoplastic
Genes, APC
Genotype
Intestinal Mucosa pathology
Intestinal Neoplasms genetics
Intestinal Neoplasms pathology
Mice
Mice, Inbred C57BL
Mice, Transgenic
Phenotype
Thyroid Hormone Receptors alpha genetics
Time Factors
Wnt Proteins genetics
beta Catenin metabolism
Adenoma metabolism
Cell Transformation, Neoplastic metabolism
Intestinal Mucosa metabolism
Intestinal Neoplasms metabolism
Signal Transduction genetics
Thyroid Hormone Receptors alpha metabolism
Wnt Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1528-0012
- Volume :
- 138
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Gastroenterology
- Publication Type :
- Academic Journal
- Accession number :
- 20114049
- Full Text :
- https://doi.org/10.1053/j.gastro.2010.01.041