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Mol Cancer Res. 2013 Sep;11(9):1040-50. doi: 10.1158/1541-7786.MCR-13-0084-T. Epub 2013 Jun 5.

Epithelial-specific deletion of 11β-HSD2 hinders Apcmin/+ mouse tumorigenesis.

Author information

1
Departments of Medicine and Cancer Biology, S-3206, MCN, Vanderbilt University Medical Center, Nashville, TN 37232. ming-zhi.zhang@vanderbilt.edu.

Abstract

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 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.

PMID:
23741059
PMCID:
PMC3778073
DOI:
10.1158/1541-7786.MCR-13-0084-T
[Indexed for MEDLINE]
Free PMC Article

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