Identification of the receptor, which mediates the tumor promoting effect of prostanoids, using knock-out mice.

使用基因敲除小鼠鉴定介导前列腺素类肿瘤促进作用的受体。

基本信息

批准号：
11138202
负责人：
USHIKUBI Fumitaka
金额：
$ 6.4万
依托单位：
Asahikawa Medical College
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research on Priority Areas (A)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至无数据
项目状态：
已结题

项目摘要

Because more than eighty percent of the familial colonic polyposis and sporadic colonic cancer are associated with mutations of the adenomatous polyposis coli gene (APC gene), APC gene was thought to participate in the pathogenesis of colonic cancer. On the other hand, non-steroidal anti-inflammatory drugs, which inhibit rate-limiting enzyme, cyclooxygenase-2, of the prostanoids biosynthesis, have been reported to inhibit the occurence and progression of coloic cancer. Moreover, the prostanoids have been reported to participate in the generation of the polyposis induced by azoxymethane. In this study, we intended to identify the prostanoid receptor participating in the generation of colonic cancer, and to clarify its mechanism to promote the carcinogenesis. We adopted two models to analyze the roles of the prostanoids on colonic calcinogenesis. One model is azoxymethane-induced carcinogenesis using the mice lacking each of the prostanoid receptor. The other is the model using the cross-breeding of the mice lacking each of the prostanoid receptor with mice lacking the APC gene product. Mice lacking the prostaglandin E receptor subtype EP1 showed decreased number and size of intestinal polyps when treated with azoxymethane. Moreover, mice lacking a prostaniod receptor cross-breeded with mice lacking the APC gene product had decreased number of intestinal polyps. These results show that some prostanoids via their cell-surface receptors play an immportant role in the carcinogenesis of the colon.

由于超过百分之八十的家族性结肠息肉病和散发性结肠癌与腺瘤性息肉病结肠基因（APC基因）的突变有关，因此据认为APC基因参与了结肠癌的发病机理。另一方面，据报道，抑制前类动物生物合成的非甾体类抗炎药，可抑制限速酶，环氧酶-2的环氧酶-2，可抑制coloic癌的发生和进展。此外，据报道，前列腺素参与甲氧甲烷诱导的多杂交的产生。在这项研究中，我们旨在确定参与结肠癌产生的前类样受体，并阐明其促进癌变的机制。我们采用了两个模型来分析前列腺素对结肠钙化的作用。一个模型是使用缺乏前列腺素受体的小鼠甲氧基甲烷诱导的致癌作用。另一个是使用缺乏APC基因产物的小鼠的小鼠的小鼠的杂交模型。缺乏前列腺素E受体亚型EP1的小鼠在用甲氧甲烷治疗时显示出肠息肉的数量和大小降低。此外，缺乏前列腺素受体交叉杂交的小鼠缺乏APC基因产物的小鼠的肠道息肉数量降低。这些结果表明，一些通过其细胞表面受体的前列腺素在结肠的致癌作用中起着不重要的作用。