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

由于80%以上的家族性结肠息肉病和散发性结肠癌都与大肠腺瘤性息肉病基因（APC基因）的突变有关，因此APC基因被认为参与了结肠癌的发病机制。另一方面，非甾体类抗炎药抑制前列腺素生物合成的限速酶环氧化酶-2，已被报道可抑制结肠直肠癌的发生和进展。此外，有报道称类前列腺素参与偶氮甲烷诱导的息肉病的产生。本研究旨在鉴定参与结肠癌发生的前列腺素受体，并阐明其促进结肠癌发生的机制。我们采用两种模型分析前列腺素在结肠钙质生成中的作用。一种模型是用缺乏前列腺素受体的小鼠进行偶氮甲烷诱导的癌变。另一种是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的小鼠在偶氮氧甲烷处理后，肠息肉的数量和大小均减少。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。这些结果表明，一些前列腺素通过其细胞表面受体在结肠的癌变中起重要作用。

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.