Increased expression of the thyroid hormone nuclear receptor TRα1 characterizes intestinal tumors with high Wnt activity.
Fiche publication
Date publication
juillet 2018
Journal
Oncotarget
Auteurs
Membres identifiés du Cancéropôle Est :
Dr PLATEROTI Michelina
Tous les auteurs :
Uchuya-Castillo J, Aznar N, Frau C, Martinez P, Le Nevé C, Marisa L, Penalva LOF, Laurent-Puig P, Puisieux A, Scoazec JY, Samarut J, Ansieau S, Plateroti M
Lien Pubmed
Résumé
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 the Wnt and Notch pathways. Importantly, increased expression of TRα1 in the intestinal epithelium in a mutated genetic background (-TRα1/Apc mice) accelerated tumorigenesis and contributed to a more aggressive tumor phenotype compared to that of the 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 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 , and . 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.
Mots clés
Wnt antagonist, Wnt pathway, intestinal cancer, thyroid hormone, thyroid hormone nuclear receptor
Référence
Oncotarget. 2018 Jul 24;9(57):30979-30996