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

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 11?-hydroxysteroid dehydrogenase type II (11?-HSD2)-mediated metabolism. Previously, it was reported that 11?-HSD2 is increased in human colonic and Apc(min/+) mouse intestinal adenomas and correlated with increased COX-2, and 11?-HSD2 inhibition suppressed the COX-2 pathway and decreased tumorigenesis. Because 11?-HSD2 is expressed in Apc(min/+) mouse intestinal adenoma stromal and epithelial cells, Apc(min/+) mice were generated with selective deletion of 11?-HSD2 in intestinal epithelial cells (Vil-Cre-HSD2(-/-) Apc(min/+)). Deletion of 11?-HSD2 in intestinal epithelia led to marked inhibition of Apc(min/+) mouse intestinal tumorigenesis. Immunostaining indicated decreased 11?-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 11?-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 11?-HSD2 may represent a novel approach for colorectal cancer chemoprevention by increasing tumor glucocorticoid activity, which in turn inhibits tumor growth by multiple pathways.

SUBMITTER: Jiang L

PROVIDER: S-EPMC3778073 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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

Jiang Li L Yang Shilin S Yin Huiyong H Fan Xiaofeng X Wang Suwan S Yao Bing B Pozzi Ambra A Chen Xiaoping X Harris Raymond C RC Zhang Ming-Zhi MZ

Molecular cancer research : MCR 20130605 9

<h4>Unlabelled</h4>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 decr ...[more]

PMID: 23741059

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Project description:Epigenetic modulators, particularly histone deacetylases (HDACs), are valid targets for cancer prevention and therapy. Recent studies report that HDAC2 overexpression is associated with colon tumor progression and is a potential target for colon cancer prevention. This study tested chemopreventive and dose-response effects of Ohio State University HDAC42 (OSU-HDAC42), a selective HDAC2 inhibitor, using a rat colon carcinogenesis model to assess aberrant crypt foci inhibition and a familial adenomatous polyposis model to assess intestinal tumor inhibition. Colonic aberrant crypt foci were induced by azoxymethane (AOM) (15 mg/kg body weight, once-weekly subcutaneous injections at 8 and 9 weeks age). One week after AOM treatment, groups of rats were fed an AIN-76A diet containing 0, 75, 150, and 300 ppm OSU-HDAC42 for 8 weeks, and colonic aberrant crypt foci were evaluated. To assess the inhibitory effect of OSU-HDAC42 on small-intestinal polyps and colon tumor growth, 6-week-old male C57Bl/6J-APC(min/+)mice were fed an AIN-76A diet containing 150 ppm OSU-HADC42 or 300 ppm pan-HDAC inhibitor suberoylanilide hydroxyamic acid (SAHA) for 80 days. Our results demonstrate that dietary OSU-HDAC42 produced dose-dependent inhibition of AOM-induced colonic aberrant crypt foci formation (13-50%; P < 0.01 to < 0.0001) and reduced multiple crypts with ≥ 4 crypts per focus (25-57%; P < 0.01 to < 0.0001) in F344 rats. Our findings show that 150 ppm OSU-HDAC42 significantly inhibited small-intestinal polyps (>46%; P < 0.001), with polyp size measuring >1 mm (P < 0.001), and colon tumors (>26%) in APC(min/+)mice, whereas 300 ppm SAHA showed nonsignificant inhibition. Mice fed 150 ppm OSU-HDAC42 had significantly decreased HDAC2, proliferating cell nuclear antigen, B cell lymphoma 2, cyclin-dependent kinase 2, and cell division cycle homolog 25C expression levels and increased p53 expression levels. These observations demonstrate the chemopreventive efficacy of OSU-HDAC42 against chemically induced and polyposis models of intestinal tumorigenesis.

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

Publications

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

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