15-Hydroxyprostaglandin dehydrogenase is an in vivo suppressor of colon tumorigenesis

Abstract

15-Hydroxyprostaglandin dehydrogenase (15-PGDH)is a prostaglandin-degrading enzyme that is highly expressed in normal colon mucosa but is ubiquitously lost in human colon cancers. Herein, we demonstrate that 15-PGDH is active in vivo as a highly potent suppressor of colon neoplasia development and acts in the colon as a required physiologic antagonist of the prostaglandin-synthesizing activity of the cyclooxygenase 2 (COX-2) oncogene. We first show that 15-PGDH gene knockout induces a marked 7.6-fold increase in colon tumors arising in the Min (multiple intestinal neoplasia) mouse model. Furthermore, 15-PGDH gene knockout abrogates the normal resistance of C57BL͞6J mice to colon tumor induction by the carcinogen azoxymethane (AOM), conferring susceptibility to AOM-induced adenomas and carcinomas in situ. Susceptibility to AOM-induced tumorigenesis is mediated by a marked induction of dysplasia, proliferation, and cyclin D1 expression throughout microscopic aberrant crypt foci arising in 15-PGDH null colons and is concomitant with a doubling of prostaglandin E 2 in 15-PGDH null colonic mucosa. A parallel role for 15-PGDH loss in promoting the earliest steps of colon neoplasia in humans is supported by our finding of a universal loss of 15-PGDH expression in microscopic colon adenomas recovered from patients with familial adenomatous polyposis, including adenomas as small as a single crypt. These models thus delineate the in vivo significance of 15-PGDH-mediated negative regulation of the COX-2 pathway and moreover reveal the particular importance of 15-PGDH in opposing the neoplastic progression of colonic aberrant crypt foci.colon cancer ͉ prostaglandin E2 T he first and rate-limiting step in the inactivation and degradation of prostaglandins is catalyzed by the enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) (1). Studies by our group and by others have demonstrated that 15-PGDH is highly expressed by normal colonic epithelial cells residing in the luminal regions of colonic crypts but that transcription of 15-PGDH mRNA is ubiquitously lost in colon cancers (2, 3). These findings have suggested the hypothesis that 15-PGDH could be a candidate tumor suppressor gene (2, 3) that might, in the normal colon, act to antagonize the prostaglandingenerating activity of the cyclooxygenase 2 (COX-2) oncogene (4). Transcriptional up-regulation of COX-2 is thought to contribute to the genesis of up to 85% of all human colon cancers (4), with the oncogenic activity of COX-2 having been demonstrated in multiple different in vivo models (5-7) and by the activity of COX-2-inhibitory drugs in shrinking premalignant human colonic adenomas (4, 8). Although negative regulation of the COX-2 pathway by 15-PGDH could thus be of clear potential significance to colon carcinogenesis, the hypothesized tumor suppressor activity of 15-PGDH has thus far not been tested in vivo. We therefore embarked on a series of studies designed to test the in vivo potency of 15-PGDH as a colon tumor suppressor by using the 15-PGDH knockout mouse as ...

Inflammatory Mediators and Nuclear Receptor Signaling in Colorectal Cancer

“…17,32 Furthermore, elevated endogenous PGE 2 via loss of 15-PGDH promotes colon tumor growth in Apc Min/+ and AOM mouse models. 33 These findings provide direct evidence supporting the central role of PGE 2 in promoting cancer progression. The biological function of PGE 2 in colorectal tumorigenesis has been further confirmed by using homozygous deletion of PGE 2 receptors.…”

The inflammatory network in the gastrointestinal tumor microenvironment: lessons from mouse models

“…Expression of COX-2 and mPGES-1 is detected predominantly in stromal cells, including macrophages and fibroblasts, but not in the epithelial cells of mouse intestinal polyps, and the same is true for human colon polyps [36,[50][51][52]. Heterozygous mutations in the Lkb1, Smad4, or Cdx2 gene lead to the development of gastrointestinal hamartomas, which show distinct histological characteristics from dysplastic adenomas developed in Apc mutant mice [52][53][54][55].…”

Mammary Gland Density Predicts the Cancer Inhibitory Activity of the N-3 to N-6 Ratio of Dietary Fat

“…However, the effects on plasma fatty acid concentrations require not only additional studies of eicosanoid synthesis but also eicosanoid degradation because the levels of eicosapentaenoic acid and docosahexaenoic acid actually decreased numerically with increasing n-3:n-6 ratio above 5:1. The possibility that fatty acid degradation is induced is noteworthy given recent reports that eicosanoid elimination is associated with tumor suppressor activity (39)(40)(41)(42)(43). Also warranted by the plasma fatty acid data are studies of hepatic, adipose, and muscle lipid metabolism in response to the ratio with a particular focus on lipid oxidation and detoxification mechanisms.…”