Mice carrying an epithelial deletion of the glucocorticoid receptor NR3C1 develop a higher tumor load in experimental colitis associated cancer

Abstract

The glucocorticoid receptor NR3C1 is expressed in multiple cell types in the gut and elsewhere. Intestinal epithelial cells both produce and respond to glucocorticoids in different physiological and pathological contexts. In experimental colitis glucocorticoids have been shown to exert a dual role, dampening inflammation while producing a deterioration in animal status, including death. Mice with tamoxifen inducible, intestinal epithelial specific deletion of NR3C1 (NR3C1IEC mice) are protected against experimental colitis, suggesting glucocorticoid epithelial actions are deleterious. Since glucocorticoids modulate epithelial proliferation it follows that they may affect the development of colon cancer. In this study we set out to test this hypothesis using the dextran sulfate sodium - azoxymethane model of colitis-associated cancer. KO mice were found to exhibit a 2-fold higher tumor load but similar incidence and tumor size. Tumors had a higher trend to extend to the submucosal layer (36% vs. 0%) in NR3C1IEC mice, and overexpressed Lgr5, Egfr and Myc, consistent with increased proliferation and neoplastic transformation. Snai1 and Snai2 were upregulated specifically in tumors of NR3C1ΔIEC mice, suggesting enhanced epithelial to mesenchymal transition in the absence of the intestinal epithelial GC receptor. We conclude that endogenous GC epithelial signaling is involved in colitis associated cancer.