Sonoshita M, Takaku K, Sasaki N, Sugimoto Y, Ushikubi F, Narumiya S, Oshima M, Taketo M M
Laboratory of Biomedical Genetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan.
Nat Med. 2001 Sep;7(9):1048-51. doi: 10.1038/nm0901-1048.
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.
花生四烯酸通过环氧化酶（COX）代谢为前列腺素H2（PGH2）。COX-2是一种诱导型COX同工酶，在肠道息肉病中起关键作用。在PGH2的代谢产物中，PGE2与肿瘤发生有关，因为其水平在肠道腺瘤和结肠癌组织中显著升高。在这里，我们表明编码PGE2细胞表面受体EP2的基因纯合缺失会导致Apc（Delta 716）小鼠（一种人类家族性腺瘤性息肉病的小鼠模型）肠道息肉的数量和大小减少。这种效应与COX-2基因破坏的效应相似。我们还表明，PGE2通过EP2受体通过正反馈回路促进COX-2的表达。其他PGE2受体EP1或EP3的纯合基因敲除对Apc（Delta 716）小鼠的肠道息肉形成没有影响。我们得出结论，EP2是介导肠道息肉病中COX-2上调产生的PGE2信号的主要受体，并且细胞内cAMP的增加会刺激息肉基质中更多COX-2和血管内皮生长因子的表达。
