Epithelial-specific deletion of 11β-HSD2 hinders apc^min/+ mouse tumorigenesis

Cyclooxygenase-2 (COX-2)-derived prostaglandin E2 (PGE2) promotes colorectal tumorigenesis. Glucocorticoids are endogenous and potent COX-2 inhibitors, and their local actions are downregulated by 11βhydroxysteroid dehydrogenase type II (11β-HSD2)-mediated metabolism. Previously, it was reported that 11β-HSD2 is increased in human colonic and Apc ^min/+ mouse intestinal adenomas and correlated with increased COX-2, and 11β-HSD2 inhibition suppressed the COX-2 pathway and decreased tumorigenesis. Because 11β- HSD2 is expressed in Apc^min/+ mouse intestinal adenoma stromal and epithelial cells, Apc^min/+ mice were generated with selective deletion of 11β-HSD2 in intestinal epithelial cells (Vil-Cre-HSD2^-/- Apc^min/+). Deletion of 11β-HSD2 in intestinal epithelia led to marked inhibition of Apc ^min/+ mouse intestinal tumorigenesis. Immunostaining indicated decreased 11β-HSD2 and COX-2 expression in adenoma epithelia, whereas stromal COX-2 expression was intact in Vil-Cre-HSD2^-/- Apc ^min/+ mice. In Vil-Cre-HSD2^-/- Apc^min/+ mouse intestinal adenomas, both p53 and p21 mRNA and protein were increased, with a concomitant decrease in pRb, indicating glucocorticoid-mediated G1-arrest. Further study revealed that REDD1 (regulated in development and DNA damage responses 1), a novel stress-induced gene that inhibits mTOR signaling, was increased, whereas the mTOR signaling pathway was inhibited. Therefore, in Vil-Cre-HSD2^-/- Apc^min/+ mice, epithelial cell 11β-HSD2 deficiency leads to inhibition of adenoma initiation and growth by attenuation of COX-2 expression, increased cell-cycle arrest, and inhibition of mTOR signaling as a result of increased tumor intracellular active glucocorticoids. Implications: Inhibition of 11β-HSD2 may represent a novel approach for colorectal cancer chemoprevention by increasing tumor glucocorticoid activity, which in turn inhibits tumor growth by multiple pathways. © 2013 American Association for Cancer Research.