Acceleration of intestinal polyposis through prostaglandin receptor EP2 in ApcΔ716 knockout mice
Acceleration of intestinal polyposis through prostaglandin receptor EP2 in ApcΔ716 knockout mice
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DOI：
10.1038/nm0901-1048
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发表时间：
2001-09-01
期刊：
影响因子：
82.9
通讯作者：
Taketo, MM
中科院分区：
文献类型：
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作者：
Sonoshita, M;Takaku, K;Taketo, MM
花生四烯酸通过环氧合酶（考克斯）代谢为前列腺素H-2（PGH（2））。考克斯-2是一种诱导型考克斯同工酶，在肠息肉病中起关键作用（1，2）。在PGH的代谢产物中，PGE与肿瘤发生有关，因为其水平在肠腺瘤和结肠癌组织中显著升高（3）。在这里，我们表明，编码PGE（2）的细胞表面受体EP 2的基因的纯合缺失，导致Apc（Delta 716）小鼠（人类家族性腺瘤性息肉病的小鼠模型）肠息肉的数量和大小减少。这种作用与考克斯-2基因破坏的作用相似。我们还发现PGE（2）通过EP 2受体通过正反馈环促进考克斯-2的表达。敲除其他PGE（2）受体EP 1或EP 3的纯合基因对Apc（Delta 716）小鼠肠息肉的形成没有影响。我们的结论是，EP 2是肠息肉中考克斯-2上调产生的PGE（2）信号的主要受体，并且增加的细胞cAMP刺激息肉基质中更多的考克斯-2和血管内皮生长因子的表达。
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(1,2). Among the metabolites of PGH,, PGE, is implicated in tumorigenesis because its level is markedly elevated in tissues of intestinal adenoma and colon cancer(3). 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 PGE(2) 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.