Increased expression of the thyroid hormone nuclear receptor TRα1 characterizes intestinal tumors with high Wnt activity

Abstract

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.

Murine intestinal stem cells are highly sensitive to modulation of the T3/TRα1-dependent pathway

“…Upon T3 binding, TRs undergo a conformational change enabling activation or repression of the transcriptional machinery (Brent, 2012). TRα1 is specifically expressed in intestinal crypt cells (Kress et al, 2009(Kress et al, , 2010, in which it acts as a direct activator of Wnt (Kress et al, 2009;Plateroti et al, 2006) and Notch pathways (Sirakov et al, 2015), as well as of cell proliferation (Kress et al, 2009(Kress et al, , 2010Uchuya-Castillo et al, 2018). These data are consistent with the phenotype described in TRα-knockout animals or in TRα1overexpressing mice (Kress et al, 2009(Kress et al, , 2010Plateroti et al, 2001Plateroti et al, , 2006.…”

“…The expression of a dominant negative TRα1 strongly affects organoid growth ex vivo TRα1 has been shown to play a pivotal role in the intestinal crypt pathophysiology (Bao et al, 2019;Sirakov and Plateroti, 2011;Uchuya-Castillo et al, 2018). Using TRα1 L400R mice (hereafter designated as TRami), corresponding to a model of TRα1 loss-offunction (Quignodon et al, 2007), we analyzed the effects of inducing the TRα1 mutation on ex vivo 3D organoid growth and structuration.…”

MicroRNA-Assisted Hormone Cell Signaling in Colorectal Cancer Resistance

“…Overexpression of TRβ1 induces a reduction of inactivated Akt, disrupting its pathway and suppressing CRC cell progression and migration [ 71 ]. In contrast, TRα1 overexpression and Wnt signaling pathway upregulation promote tumor formation in CRC [ 72 ] by contributing to escape from chemotherapy-induced apoptosis [ 73 ]. Indeed, further evidence report that T3 affects drug resistance targeting BMP4/Wnt pathway [ 70 ].…”

Non-genomic Actions of Thyroid Hormones Regulate the Growth and Angiogenesis of T Cell Lymphomas

“…Thus, the mutation (86, 87) or aberrant expression (88) of TRs has been demonstrated in several cancer cell lines. Also, biopsies of patients with gastrointestinal tumors showed increased levels of TRα1 that correlate with Wnt pathway activation and tumor proliferation (89).…”