ß-Catenin regulates deiodinase levels and thyroid hormone signaling in colon cancer cells.
Gastroenterology
; 143(4): 1037-47, 2012 Oct.
Article
em En
| MEDLINE
| ID: mdl-22771508
ABSTRACT
BACKGROUND & AIMS:
Activation of the ß-catenin/T-cell factor (TCF) complex occurs in most colon tumors, and its actions correlate with the neoplastic phenotype of intestinal epithelial cells. Type 3 deiodinase (D3), the selenoenzyme that inactivates thyroid hormone (3,5,3' triiodothyronine [T3]), is frequently expressed by tumor cells, but little is known about its role in the regulation of T3 signaling in cancer cells.METHODS:
We measured D3 expression in 6 colon cancer cell lines and human tumors and correlated it with the activity of the ß-catenin/TCF complex. We also determined the effects of D3 loss on local thyroid hormone signaling and colon tumorigenesis.RESULTS:
We show that D3 is a direct transcriptional target of the ß-catenin/TCF complex; its expression was higher in human intestinal adenomas and carcinomas than in healthy intestinal tissue. Experimental attenuation of ß-catenin reduced D3 levels and induced type 2 deiodinase (the D3 antagonist that converts 3,5,3',5' tetraiodothyronine into active T3) thereby increasing T3-dependent transcription. In the absence of D3, excess T3 reduced cell proliferation and promoted differentiation in cultured cells and in xenograft mouse models. This occurred via induction of E-cadherin, which sequestered ß-catenin at the plasma membrane and promoted cell differentiation.CONCLUSIONS:
Deiodinases are at the interface between the ß-catenin and the thyroid hormone pathways. Their synchronized regulation of intracellular T3 concentration is a hitherto unrecognized route by which the multiple effects of ß-catenin are generated and may be targeted to reduce the oncogenic effects of ß-catenin in intestinal cells.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Tri-Iodotironina
/
Carcinoma
/
Adenoma
/
Neoplasias do Colo
/
Beta Catenina
/
Via de Sinalização Wnt
/
Iodeto Peroxidase
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Female
/
Humans
Idioma:
En
Revista:
Gastroenterology
Ano de publicação:
2012
Tipo de documento:
Article
País de afiliação:
Itália