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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 11-beta-Hydroxysteroid Dehydrogenase Type 2 / antagonists & inhibitors
  • 11-beta-Hydroxysteroid Dehydrogenase Type 2 / genetics*
  • 11-beta-Hydroxysteroid Dehydrogenase Type 2 / metabolism*
  • Adenoma / genetics
  • Adenoma / metabolism
  • Adenoma / pathology*
  • Animals
  • Carcinogenesis*
  • Cell Cycle
  • Cell Line, Tumor
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / pathology*
  • Corticosterone / metabolism
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Cyclooxygenase 2 / biosynthesis
  • Cyclooxygenase 2 / genetics*
  • Disease Models, Animal
  • Gene Expression Regulation, Neoplastic
  • Genes, APC*
  • Humans
  • Intestinal Mucosa / metabolism
  • Intestinal Mucosa / pathology
  • Mice
  • Mice, Inbred C57BL
  • Sequence Deletion
  • TOR Serine-Threonine Kinases / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Cyclin-Dependent Kinase Inhibitor p21
  • Ddit4 protein, mouse
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • 11-beta-Hydroxysteroid Dehydrogenase Type 2
  • Cyclooxygenase 2
  • TOR Serine-Threonine Kinases
  • Corticosterone