title: Cooperation between the thyroid hormone receptor TRalpha1 and the WNT pathway in the induction of intestinal tumorigenesis.
abstract: 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.
authors.affiliation: Institut de Génomique Fonctionnelle de Lyon, Université de Lyon, Université Lyon 1, CNRS, INRA, Ecole Normale Supérieure de Lyon, Lyon, France.
authors.forename: Elsa
authors.initials: E
authors.lastname: Kress
authors.forename: Seham
authors.initials: S
authors.lastname: Skah
authors.forename: Maria
authors.initials: M
authors.lastname: Sirakov
authors.forename: Julien
authors.initials: J
authors.lastname: Nadjar
authors.forename: Nicolas
authors.initials: N
authors.lastname: Gadot
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Scoazec
authors.forename: Jacques
authors.initials: J
authors.lastname: Samarut
authors.forename: Michelina
authors.initials: M
authors.lastname: Plateroti
mesh_terms: 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
chemical_list: C495267:CTNNB1 protein, mouse; D037021:Thyroid Hormone Receptors alpha; D051153:Wnt Proteins; D051176:beta Catenin