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

Seung Jae Myung, Ronald M. Rerko, Min Yan, Petra Platzer, Kishore Guda, Angela Dotson, Earl Lawrence, Andrew J. Dannenberg, Alysia Kern Lovgren, Guangbin Luo, Theresa P. Pretlow, Robert A. Newman, Joseph Willis, Dawn Dawson, Sanford D. Markowitz

Research output: Contribution to journalArticle

196 Scopus citations

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 C57BL/6J 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 E2 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.

Original languageEnglish (US)
Pages (from-to)12098-12102
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number32
DOIs
StatePublished - Aug 8 2006

Keywords

  • Colon cancer
  • Prostaglandin E

ASJC Scopus subject areas

  • Genetics
  • General

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