Li Jiang, Shilin Yang, Huiyong Yin, Xiaofeng Fan, Suwan Wang, Bing Yao, Ambra Pozzi, Xiaoping Chen, Raymond C. Harris, and Ming-Zhi Zhang
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 11β-hydroxysteroid dehydrogenase type II (11β-HSD2)-mediated metabolism. Previously, it was reported that 11β-HSD2 is increased in human colonic and Apcmin/+ 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 Apcmin/+ mouse intestinal adenoma stromal and epithelial cells, Apcmin/+ mice were generated with selective deletion of 11β-HSD2 in intestinal epithelial cells (Vil-Cre-HSD2−/− Apcmin/+). Deletion of 11β-HSD2 in intestinal epithelia led to marked inhibition of Apcmin/+ 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−/− Apcmin/+ mice. In Vil-Cre-HSD2−/− Apcmin/+ 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−/− Apcmin/+ 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. 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.