Cooperation between the thyroid hormone receptor TRalpha1 and the WNT pathway in the induction of intestinal tumorigenesis.
OBJECTIVE
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.


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.


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.


CONCLUSIONS
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.
Kress
Elsa
E
Institut de Génomique Fonctionnelle de Lyon, Université de Lyon, Université Lyon 1, CNRS, INRA, Ecole Normale Supérieure de Lyon, Lyon, France.
Skah
Seham
S
Sirakov
Maria
M
Nadjar
Julien
J
Gadot
Nicolas
N
Scoazec
Jean-Yves
JY
Samarut
Jacques
J
Plateroti
Michelina
M
D000236:Adenoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D017491:Genes, APC; D005838:Genotype; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D007414:Intestinal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010641:Phenotype; D015398:Signal Transduction / Q000235:genetics; D037021:Thyroid Hormone Receptors alpha / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
C495267:CTNNB1 protein, mouse; D037021:Thyroid Hormone Receptors alpha; D051153:Wnt Proteins; D051176:beta Catenin