Increased expression of the thyroid hormone nuclear receptor TRα1 characterizes intestinal tumors with high Wnt activity
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Joel Uchuya-Castillo1,*, Nicolas Aznar1,*, Carla Frau1, Pierre Martinez1, Clementine Le Nevé1, Laetitia Marisa2, Luiz O.F. Penalva3, Pierre Laurent-Puig4, Alain Puisieux1, Jean-Yves Scoazec5, Jacques Samarut6, Stephane Ansieau1 and Michelina Plateroti1
1Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS UMR5286, Université de Lyon, Université Lyon 1, Centre Léon Bérard, Département de la recherche, Lyon 69000, France
2Programme Cartes d’Identité des Tumeurs (CIT), Ligue Nationale Contre le Cancer, Paris 75000, France
3Children’s Cancer Research Institute, University of Texas Health Science Center at San Antonio, TX 78229, USA
4UMR-S 1147, Université Paris Descartes, Paris 75006, France
5Institute Gustave Roussy, Villejuif 94800, France
6Institute de Génomique Fonctionnelle de Lyon, ENS de Lyon, Lyon 69342, France
*These authors contributed equally to this work
Michelina Plateroti, email: email@example.com
Keywords: intestinal cancer; thyroid hormone; thyroid hormone nuclear receptor; Wnt antagonist; Wnt pathway
Abbreviations: IB: immunoblot; IF: immunofluorescence; IHC: immunohistochemistry; PCR: polymerase chain reaction; RT: reverse transcription
Received: February 18, 2018 Accepted: June 12, 2018 Published: July 24, 2018
Our previous work demonstrated a key function of the thyroid hormone nuclear receptor TRα1, a T3-modulated transcription factor, in controlling intestinal development and homeostasis via the Wnt and Notch pathways. Importantly, increased expression of TRα1 in the intestinal epithelium in a mutated Apc genetic background (vil-TRα1/Apc+/1638N mice) accelerated tumorigenesis and contributed to a more aggressive tumor phenotype compared to that of the Apc mutants alone. Therefore, the aim of this study was to determine the relevance of this synergistic effect in human colorectal cancers and to gain insights into the mechanisms involved. We analyzed cohorts of patients by in silico and experimental approaches and observed increased TRα1 expression and a significant correlation between TRα1 levels and Wnt activity. TRα1 loss-of-function and gain-of-function in Caco2 cell lines not only confirmed that TRα1 levels control Wnt activity but also demonstrated the role of TRα1 in regulating cell proliferation and migration. Finally, upon investigation of the molecular mechanisms responsible for the Wnt-TRα1 association, we described the repression by TRα1 of several Wnt inhibitors, including Frzb, Sox17 and Wif1. In conclusion, our results underline an important functional interplay between the thyroid hormone nuclear receptor TRα1 and the canonical Wnt pathway in intestinal cancer initiation and progression. More importantly, we show for the first time that the expression of TRα1 is induced in human colorectal cancers.
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