title: β-Catenin regulates deiodinase levels and thyroid hormone signaling in colon cancer cells.
abstract: OBJECTIVE
  Activation of the β-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 β-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 β-catenin/TCF complex; its expression was higher in human intestinal adenomas and carcinomas than in healthy intestinal tissue. Experimental attenuation of β-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 β-catenin at the plasma membrane and promoted cell differentiation.
  
  
  CONCLUSIONS
  Deiodinases are at the interface between the β-catenin and the thyroid hormone pathways. Their synchronized regulation of intracellular T3 concentration is a hitherto unrecognized route by which the multiple effects of β-catenin are generated and may be targeted to reduce the oncogenic effects of β-catenin in intestinal cells.
authors: Department of Molecular and Clinical Endocrinology and Oncology, University of Naples "Federico II," Naples, Italy.
authors: Monica
authors: M
authors: Dentice
authors: Cristina
authors: C
authors: Luongo
authors: Raffaele
authors: R
authors: Ambrosio
authors: Annarita
authors: A
authors: Sibilio
authors: Antonella
authors: A
authors: Casillo
authors: Antonino
authors: A
authors: Iaccarino
authors: Giancarlo
authors: G
authors: Troncone
authors: Gianfranco
authors: G
authors: Fenzi
authors: P Reed
authors: PR
authors: Larsen
authors: Domenico
authors: D
authors: Salvatore
mesh_terms: D000236:Adenoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D000818:Animals; D018938:Caco-2 Cells; D015820:Cadherins / Q000187:drug effects / Q000378:metabolism; D002277:Carcinoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003106:Colon / Q000201:enzymology; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D045325:HCT116 Cells; D006801:Humans; D007453:Iodide Peroxidase / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010957:Plasmids; D012333:RNA, Messenger / Q000378:metabolism; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014183:Transplantation, Heterologous; D014284:Triiodothyronine / Q000378:metabolism* / Q000494:pharmacology; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism*; D000097564:Iodothyronine Deiodinase Type II
chemical_list: D015820:Cadherins; D007453:Iodide Peroxidase; D012333:RNA, Messenger; D058118:Transcription Factor 7-Like 2 Protein; D014284:Triiodothyronine; D051176:beta Catenin; D000097564:Iodothyronine Deiodinase Type II; C544894:TCF7L2 protein, human; C117274:iodothyronine deiodinase type III