Acceleration of intestinal polyposis through prostaglandin receptor EP2 in ApcΔ716 knockout mice
Author: ["Masahiro Sonoshita","Kazuaki Takaku","Nobuya Sasaki","Yukihiko Sugimoto","Fumitaka Ushikubi","Shuh Narumiya","Masanobu Oshima","Makoto M. Taketo"]
Publication: Nature Medicine
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Abstract
Arachidonic acid is metabolized to prostaglandin H2 (PGH2) by cyclooxygenase (COX). COX-2, the inducible COX isozyme, has a key role in intestinal polyposis1,2. Among the metabolites of PGH2, PGE2 is implicated in tumorigenesis because its level is markedly elevated in tissues of intestinal adenoma and colon cancer3. Here we show that homozygous deletion of the gene encoding a cell-surface receptor of PGE2, EP2, causes decreases in number and size of intestinal polyps in ApcΔ716 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 PGE2 through the EP2 receptor via a positive feedback loop. Homozygous gene knockout for other PGE2 receptors, EP1 or EP3, did not affect intestinal polyp formation in ApcΔ716 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.
Cite this article
Sonoshita, M., Takaku, K., Sasaki, N. et al. Acceleration of intestinal polyposis through prostaglandin receptor EP2 in ApcΔ716 knockout mice. Nat Med 7, 1048–1051 (2001). https://doi.org/10.1038/nm0901-1048
