title: 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 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.
authors.affiliation: Department of Medicine, Case Western Reserve University, University Hospitals of Cleveland, Cleveland, OH 44106, USA.
authors.forename: Seung-Jae
authors.initials: SJ
authors.lastname: Myung
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Rerko
authors.forename: Min
authors.initials: M
authors.lastname: Yan
authors.forename: Petra
authors.initials: P
authors.lastname: Platzer
authors.forename: Kishore
authors.initials: K
authors.lastname: Guda
authors.forename: Angela
authors.initials: A
authors.lastname: Dotson
authors.forename: Earl
authors.initials: E
authors.lastname: Lawrence
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Dannenberg
authors.forename: Alysia Kern
authors.initials: AK
authors.lastname: Lovgren
authors.forename: Guangbin
authors.initials: G
authors.lastname: Luo
authors.forename: Theresa P
authors.initials: TP
authors.lastname: Pretlow
authors.forename: Robert A
authors.initials: RA
authors.lastname: Newman
authors.forename: Joseph
authors.initials: J
authors.lastname: Willis
authors.forename: Dawn
authors.initials: D
authors.lastname: Dawson
authors.forename: Sanford D
authors.initials: SD
authors.lastname: Markowitz
mesh_terms: D000818:Animals; D001397:Azoxymethane; D002273:Carcinogens; D003106:Colon / Q000378:metabolism / Q000473:pathology; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism*; D019938:Cyclin D1 / Q000378:metabolism; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000235:genetics* / Q000502:physiology*; D019394:Ki-67 Antigen / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011462:Prostaglandins G / Q000378:metabolism
chemical_list: D002273:Carcinogens; D019394:Ki-67 Antigen; D011462:Prostaglandins G; D019938:Cyclin D1; C038291:prostaglandin G2; D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase; D001397:Azoxymethane