Cooperation Between the Thyroid Hormone Receptor TRα1 and the WNT Pathway in the Induction of Intestinal Tumorigenesis

BACKGROUND & AIMS: Colorectal tumorigenesis is a multistep process involving the alteration of oncogenes and tumor suppressor genes, leading to the deregulation of molecular pathways that govern intestinal homeostasis. We have previously shown that the thyroid hormone receptor alpha 1 (TR alpha 1) controls intestinal development and homeostasis through the WNT pathway. More precisely, TR alpha 1 directly enhances the transcription of several components of this pathway, allowing increased expression of beta-catenin/Tcf4 target genes and stimulation of cell proliferation. Because the WNT pathway is a major player in controlling intestinal homeostasis, we addressed whether the TR alpha 1 receptor has tumor-inducing potential. Methods: We generated mice overexpressing TR alpha 1 specifically in the intestinal epithelium in a wild-type (vil-TR alpha 1) or a WNT-activated (vil-TR alpha 1/Apc(+/1638N)) genetic background. RESULTS: The intestine of vil-TR alpha 1 mice presents aberrant intestinal mucosal architecture and increased cell proliferation and develops adenoma at a low rate. However, TR alpha 1 overexpression is unable to induce cancer development. On the contrary, we observed accelerated tumorigenesis in vil-TR alpha 1/Apc(+/1638N) mice compared with the Apc(+/1638N) mutants. CONCLUSION: Our results suggest that this phenotype is due to cooperation between the activated TR alpha 1 and WNT pathways. This is the first report describing the tumor-inducing function of TR alpha 1 in the intestine.