Acceleration of intestinal polyposis through prostaglandin receptor EP2 in Apc(Delta 716) knockout mice.
Arachidonic acid is metabolized to prostaglandin H(2) (PGH(2)) by cyclooxygenase (COX). COX-2, the inducible COX isozyme, has a key role in intestinal polyposis. Among the metabolites of PGH(2), PGE(2) is implicated in tumorigenesis because its level is markedly elevated in tissues of intestinal adenoma and colon cancer. Here we show that homozygous deletion of the gene encoding a cell-surface receptor of PGE(2), EP2, causes decreases in number and size of intestinal polyps in Apc(Delta 716) mice (a mouse model for human familial adenomatous polyposis). This effect is similar to that of COX-2 gene disruption. We also show that COX-2 expression is boosted by PGE(2) through the EP2 receptor via a positive feedback loop. Homozygous gene knockout for other PGE(2) receptors, EP1 or EP3, did not affect intestinal polyp formation in Apc(Delta 716) mice. We conclude that EP2 is the major receptor mediating the PGE2 signal generated by COX-2 upregulation in intestinal polyposis, and that increased cellular cAMP stimulates expression of more COX-2 and vascular endothelial growth factor in the polyp stroma.
Sonoshita
M
M
Laboratory of Biomedical Genetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan.
Takaku
K
K
Sasaki
N
N
Sugimoto
Y
Y
Ushikubi
F
F
Narumiya
S
S
Oshima
M
M
Taketo
M M
MM
D000236:Adenoma / Q000235:genetics / Q000473:pathology; D011125:Adenomatous Polyposis Coli / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000378:metabolism; D016228:Endothelial Growth Factors / Q000235:genetics; D006720:Homozygote; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D008222:Lymphokines / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism*; D011982:Receptors, Prostaglandin / Q000235:genetics / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000235:genetics* / Q000378:metabolism; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058307:Receptors, Prostaglandin E, EP2 Subtype; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
C428179:EP3C receptor; D016228:Endothelial Growth Factors; D007527:Isoenzymes; D008222:Lymphokines; C545635:PTGER1 protein, human; C545644:PTGER2 protein, human; C545636:Ptger1 protein, mouse; C545645:Ptger2 protein, mouse; D011982:Receptors, Prostaglandin; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058307:Receptors, Prostaglandin E, EP2 Subtype; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone