The Thyroid Hormone Nuclear Receptor Tra1 Plays an essential Role in intestinal Epithelium Stem Cell Physiopathology
(2020) Digestive Disease Week — Location: Virtual (2.May.2020)
Files
DDW2020abstract.pdf
Open Access - Adobe PDF
- 342.69 KB
Details
- Authors
- et. al.
- Abstract
- Background. Thyroid hormones (THs) control several aspects of gut development and homeostasis. They act through the nuclear receptors TRs, that are T3-modulated transcription factors. The paradigm is the amphibian metamorphosis, where they are responsible for gut remodeling and emergence of the stem cells (SC). In previous studies we showed that TH/ TRα1 play a fundamental role in regulating the balance between cell proliferation and cell differentiation of murine intestinal crypt cells. In accordance with this function, targeted expression of TRα1 in the epithelium (vil-TRα1 mice) is sufficient to induce aberrant and hyper-proliferative crypts and confers increased susceptibility to Apc-mutation dependent tumorigenic program (vil-TRα1/Apc mice); the reversal effect was observed in TR α-KO background (TRα0/0/Apc mice). Finally, in human colorectal cancer (CRC) from patients we observed increased TRα1 expression and a significant correlation between TR α1 levels and Wnt activity. This last result proved the translational potential of our fundamental studies to human CRC. The aim of this work was to study TH/TRα1-dependent control of SC physiopathology. Methods. We used the Lgr5-EGFP-CreERT2 mice crossed with tamoxifen inducible TRα1 loss-of-function animals (TRα1-LOF) in a WT or an Apc-mutated back- ground. To link TRα1 expression, TH levels and cancer SC biology we settled up a 3D culture system of spheroids from human colon adenocarcinoma Caco2 cells with altered TRα1 expression (TRα1 GOF/LOF). Results. Induction of TRα1-LOF in mice in vivo resulted in decreased Wnt and Notch pathways as well as of SC and proliferation markers expression. 3D organoids growth ex vivo was also strongly impaired in TR α1-LOF mice, indicating altered SC activity. In parallel, experiments on Caco2 cells showed that TR α1-GOF increased while TRα1-LOF decreased the size of spheres, strongly acting on their growth capacity. In addition, the altered growth is linked to alteration of SC markers. In conclusion, our results show that modulating TH/TRα1 has a strong effect on normal crypt SCs and on cancer SCs. Given the extremely high number of patients displaying thyroid dysfunctions and receiving deprivation/replacement therapies, even all along their life (12% of US population estimated by the American Thyroid Association), our work opens a new perspective in the study of TH/TRα1-dependent signal on the physiopathology of the intestinal SCs.
- Affiliations
Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS UMR5286, Université de Lyon, Université Lyon 1, Centre Léon Bérard, Département de la recherche, 69000 Lyon, France
Citations
Giolito, M. V., & et al. (2020). The Thyroid Hormone Nuclear Receptor Tra1 Plays an essential Role in intestinal Epithelium Stem Cell Physiopathology. Gastroenterology, 158(6), S510. https://doi.org/10.1016/s0016-5085(20)31960-0 (Original work published 2020)