PMID:11533709

Citation	Sonoshita, M, Takaku, K, Sasaki, N, Sugimoto, Y, Ushikubi, F, Narumiya, S, Oshima, M and Taketo, MM (2001) Acceleration of intestinal polyposis through prostaglandin receptor EP2 in Apc(Delta 716) knockout mice. Nat. Med. 7:1048-51
Abstract	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.
Links	PubMed Online version:10.1038/nm0901-1048
Keywords	Adenoma/genetics; Adenoma/pathology; Adenomatous Polyposis Coli/genetics; Adenomatous Polyposis Coli/pathology; Adenomatous Polyposis Coli/physiopathology; Animals; Cyclooxygenase 2; Dinoprostone/metabolism; Endothelial Growth Factors/genetics; Homozygote; Isoenzymes/genetics; Isoenzymes/metabolism; Lymphokines/genetics; Mice; Mice, Knockout; Prostaglandin-Endoperoxide Synthases/genetics; Prostaglandin-Endoperoxide Synthases/metabolism; Receptors, Prostaglandin/genetics; Receptors, Prostaglandin/metabolism; Receptors, Prostaglandin E/genetics; Receptors, Prostaglandin E/metabolism; Receptors, Prostaglandin E, EP1 Subtype; Receptors, Prostaglandin E, EP2 Subtype; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors
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