15-Hydroxyprostaglandin dehydrogenase is an in vivo suppressor of colon tumorigenesis.
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.
Myung
Seung-Jae
SJ
Department of Medicine, Case Western Reserve University, University Hospitals of Cleveland, Cleveland, OH 44106, USA.
Rerko
Ronald M
RM
Yan
Min
M
Platzer
Petra
P
Guda
Kishore
K
Dotson
Angela
A
Lawrence
Earl
E
Dannenberg
Andrew J
AJ
Lovgren
Alysia Kern
AK
Luo
Guangbin
G
Pretlow
Theresa P
TP
Newman
Robert A
RA
Willis
Joseph
J
Dawson
Dawn
D
Markowitz
Sanford D
SD
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
D002273:Carcinogens; D019394:Ki-67 Antigen; D011462:Prostaglandins G; D019938:Cyclin D1; C038291:prostaglandin G2; D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase; D001397:Azoxymethane