ROLE OF PROSTAGLANDIN H SYNTHASE 2 IN COLON CARCINOGENESIS

使用基因工程小鼠和化学物质进行结肠癌研究- 致癌物处理的动物，人群的流行病学研究， 和临床干预试验（非甾体抗炎药 非甾体类抗炎药（NSAIDS）都表明环氧合酶（考克斯）位于 导致结肠癌的常见途径考克斯的参与似乎发生 在途径的早期阶段--就在第二个等位基因丢失之后 APC的。有两种形式的考克斯;一种是在基础条件下发现的， 而另一种，考克斯-2，通常只表达于 对生长因子、肿瘤促进剂和细胞因子的反应。我们和 其他研究表明考克斯-2在腺瘤性息肉和结肠中表达 癌，这至少部分是由于组成性的 转录。该项目的目的之一是确定 异常转录，并在另一个目的是探索假设， 也有转录后调节。第三个目标，我们 将检测肠上皮细胞中考克斯-2（或考克斯-1）的过表达是否与肠上皮细胞中COX-2的表达有关。 上皮足以引起息肉和癌症，如果它是 与高脂肪饮食或其他突变的存在协同作用 常见于结肠癌（APC，p53）。 前列腺素合酶促进结肠的机制 致癌作用尚不清楚--拟南芥素可能刺激增殖 或抑制细胞凋亡。此外，这种酶可以催化 氧化的外源性物质，这可能有类似的行动。最后 由考克斯催化的反应可产生诱变剂。我们将检查每一个 使用转基因小鼠、细胞系和人体组织的这些机制，以及 细胞生物学、分子生物学和 生物化学 经过充分研究的廉价药物（NSAIDS）可以 减少结肠息肉和癌症的发病率提供了一个令人兴奋的 化学预防的机会。本建议旨在阐明 这种影响发生的机制，并应开辟新的途径， 预防结肠癌。

Studies of colon cancer using genetically engineered mice and chemical- carcinogen treated animals, epidemiological studies of human populations, and clinical intervention trials (with non-steroidal anti-inflammatory drugs; NSAIDS) all indicate that cyclooxygenase (COX) lies on the most common pathway to colon cancer. The participation of COX appears to occur at an early stage in the pathway-just after the loss of the second allele of APC. There are two forms of COX; one is found under basal conditions in many cells and tissue, while the other, COX-2, is usually expressed only in response to growth factors, tumor promoters, and cytokines. We and others have shown that COX-2 is expressed in adenomatous polyps and colon carcinoma, and that this results at least in part from constitutive transcription. One aim of this project is to define the mechanisms for the abnormal transcription, and in another aim to explore the hypothesis that there is post-transcriptional regulation as well. In the third aim, we will test whether over-expression of COX-2 (or COX-1) in intestinal epithelium is sufficient to cause polyps and cancer, and if it is synergistic with a high fat diet or the presence of other mutations commonly found in colon cancer (APC, p53). The mechanism by which prostaglandin synthase promotes colon carcinogenesis is not known-prostaglandins might stimulate proliferation or inhibit apoptosis. Additionally, this enzyme(s) can catalyze the oxidation of xenobiotics, which might have analogous actions. Finally, the reactions catalyzed by COX can generate mutagens. We will examine each of these mechanisms using transgenic mice, cell lines, and human tissues, and technical approaches from cell biology, molecular biology, and biochemistry. The observations that well studied, inexpensive drugs (NSAIDS) can decrease the incidence of colon polyps and cancer offers an exciting opportunity for chemoprevention. This proposal seeks to elucidate the mechanisms by which this effect occurs and should open new approaches to prevention of colon cancer.