β-catenin regulates deiodinase levels and thyroid hormone signaling in colon cancer cells

Monica Dentice, Cristina Luongo, Raffaele Ambrosio, Annarita Sibilio, Antonella Casillo, Antonino Iaccarino, Giancarlo Troncone, Gianfranco Fenzi, P. Reed Larsen, Domenico Salvatore

Research output: Contribution to journalArticle

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Abstract

BACKGROUND & AIMS: 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.

Original languageEnglish
Pages (from-to)1037-1047
Number of pages11
JournalGastroenterology
Volume143
Issue number4
DOIs
Publication statusPublished - Oct 2012

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Catenins
Iodide Peroxidase
Thyroid Hormones
Colonic Neoplasms
TCF Transcription Factors
Colon
Neoplasms
Triiodothyronine
Cadherins
Tumor Cell Line
Heterografts
Adenoma
Cell Differentiation
Cultured Cells
Carcinogenesis
Epithelial Cells
Cell Proliferation
Cell Membrane
Carcinoma
Phenotype

Keywords

  • Colorectal Cancer
  • Hypothalamus
  • Intestinal Epithelium
  • Thyroid Receptor

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Dentice, M., Luongo, C., Ambrosio, R., Sibilio, A., Casillo, A., Iaccarino, A., ... Salvatore, D. (2012). β-catenin regulates deiodinase levels and thyroid hormone signaling in colon cancer cells. Gastroenterology, 143(4), 1037-1047. https://doi.org/10.1053/j.gastro.2012.06.042

β-catenin regulates deiodinase levels and thyroid hormone signaling in colon cancer cells. / Dentice, Monica; Luongo, Cristina; Ambrosio, Raffaele; Sibilio, Annarita; Casillo, Antonella; Iaccarino, Antonino; Troncone, Giancarlo; Fenzi, Gianfranco; Larsen, P. Reed; Salvatore, Domenico.

In: Gastroenterology, Vol. 143, No. 4, 10.2012, p. 1037-1047.

Research output: Contribution to journalArticle

Dentice, M, Luongo, C, Ambrosio, R, Sibilio, A, Casillo, A, Iaccarino, A, Troncone, G, Fenzi, G, Larsen, PR & Salvatore, D 2012, 'β-catenin regulates deiodinase levels and thyroid hormone signaling in colon cancer cells', Gastroenterology, vol. 143, no. 4, pp. 1037-1047. https://doi.org/10.1053/j.gastro.2012.06.042
Dentice, Monica ; Luongo, Cristina ; Ambrosio, Raffaele ; Sibilio, Annarita ; Casillo, Antonella ; Iaccarino, Antonino ; Troncone, Giancarlo ; Fenzi, Gianfranco ; Larsen, P. Reed ; Salvatore, Domenico. / β-catenin regulates deiodinase levels and thyroid hormone signaling in colon cancer cells. In: Gastroenterology. 2012 ; Vol. 143, No. 4. pp. 1037-1047.
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AU - Dentice, Monica

AU - Luongo, Cristina

AU - Ambrosio, Raffaele

AU - Sibilio, Annarita

AU - Casillo, Antonella

AU - Iaccarino, Antonino

AU - Troncone, Giancarlo

AU - Fenzi, Gianfranco

AU - Larsen, P. Reed

AU - Salvatore, Domenico

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N2 - BACKGROUND & AIMS: 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.

AB - BACKGROUND & AIMS: 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.

KW - Colorectal Cancer

KW - Hypothalamus

KW - Intestinal Epithelium

KW - Thyroid Receptor

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