Increased expression of the thyroid hormone nuclear receptor TRa1 characterizes intestinal tumors with high Wnt activity

Our previous work demonstrated a key function of the thyroid hormone nuclear receptor TRa1, a T3-modulated transcription factor, in controlling intestinal development and homeostasis via the Wnt and Notch pathways. Importantly, increased expression of TRa1 in the intestinal epithelium in a mutated Apc genetic background (vil-TRa1/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 TRa1 expression and a significant correlation between TRa1 levels and Wnt activity. TRa1 loss-of-function and gain-of-function in Caco2 cell lines not only confirmed that TRa1 levels control Wnt activity but also demonstrated the role of TRa1 in regulating cell proliferation and migration. Finally, upon investigation of the molecular mechanisms responsible for the Wnt-TRa1 association, we described the repression by TRa1 of several Wnt inhibitors, including Frzb, Sox17 and Wif1. In conclusion, our results underline an important functional interplay between the thyroid hormone nuclear receptor TRa1 and the canonical Wnt pathway in intestinal cancer initiation and progression. More importantly, we show for the first time that the expression of TRa1 is induced in human colorectal cancers.