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

Proc Natl Acad Sci U S A. 2006 Aug 8;103(32):12098-102. doi: 10.1073/pnas.0603235103. Epub 2006 Jul 31.

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 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.

Publication types

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

MeSH terms

  • Animals
  • Azoxymethane
  • Carcinogens
  • Colon / metabolism
  • Colon / pathology
  • Colonic Neoplasms / chemically induced
  • Colonic Neoplasms / genetics*
  • Colonic Neoplasms / metabolism*
  • Cyclin D1 / metabolism
  • Humans
  • Hydroxyprostaglandin Dehydrogenases / genetics*
  • Hydroxyprostaglandin Dehydrogenases / physiology*
  • Ki-67 Antigen / biosynthesis
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Prostaglandins G / metabolism

Substances

  • Carcinogens
  • Ki-67 Antigen
  • Prostaglandins G
  • Cyclin D1
  • prostaglandin G2
  • Hydroxyprostaglandin Dehydrogenases
  • 15-hydroxyprostaglandin dehydrogenase
  • Azoxymethane