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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.

由于百分之八十以上的家族性结肠息肉病和散发性结肠癌与腺瘤性息肉病大肠杆菌基因（APC基因）突变有关，因此APC基因被认为参与了结肠癌的发病机制。另一方面，非甾体类抗炎药可抑制前列腺素生物合成的限速酶环氧合酶-2，据报道可抑制结肠癌的发生和进展。此外，据报道前列腺素类参与氧化偶氮甲烷诱导的息肉病的发生。本研究旨在鉴定参与结肠癌发生的前列腺素受体，并阐明其促进癌变的机制。我们采用两种模型来分析前列腺素类药物对结肠钙化生成的作用。一种模型是使用缺乏每种前列腺素受体的小鼠进行氧化偶氮甲烷诱导的致癌作用。另一种是使用缺乏前列腺素受体的小鼠与缺乏APC基因产物的小鼠杂交的模型。缺乏前列腺素 E 受体亚型 EP1 的小鼠在接受氧化偶氮甲烷治疗后，肠息肉的数量和大小均有所减少。此外，缺乏前列腺素受体的小鼠与缺乏APC基因产物的小鼠杂交后，肠息肉的数量减少了。这些结果表明，一些前列腺素通过其细胞表面受体在结肠癌发生中发挥重要作用。