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

María Arredondo-Amador, Raquel González, Carlos J. Aranda, Olga Martínez-Augustin, Fermín Sánchez de Medina

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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 (NR3C1DIEC 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. Knockout (KO) mice were found to exhibit a twofold higher tumor load but similar incidence and tumor size. Tumors had a higher trend to extend close to the submucosal layer (36% vs. 0%) in NR3C1DIEC mice, and overexpressed Lgr5, Egfr, and Myc, consistent with distinct expression of proliferative/stemness markers. Snai1 and Snai2 were upregulated specifically in tumors of NR3C1DIEC mice, suggesting enhanced epithelial to mesenchymal transition in the absence of the intestinal epithelial glucocorticoid (GC) receptor. We conclude that endogenous GC epithelial signaling is involved in colitis-associated cancer.

Original languageEnglish
Pages (from-to)G705-G718
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume321
Issue number6
DOIs
StatePublished - Dec 2021
Externally publishedYes

Keywords

  • Azoxymethane
  • Dextran sulfate sodium
  • Glucocorticoid
  • Intestinal steroidogenesis

Fingerprint

Dive into the research topics of 'Mice carrying an epithelial deletion of the glucocorticoid receptor NR3C1 develop a higher tumor load in experimental colitis-associated cancer'. Together they form a unique fingerprint.

Cite this