ROLE OF PROSTAGLANDIN H SYNTHASE 2 IN COLON CARCINOGENESIS

利用基因工程小鼠和化学药物研究结肠癌 用致癌物治疗的动物，人类种群的流行病学研究， 和临床干预试验(非类固醇抗炎 药物；非甾体抗炎药)都表明环氧合酶(COX)是最常见的 结肠癌的常见途径。考克斯的参与似乎正在发生 在途径的早期阶段--就在第二个等位基因丢失之后 APC的。COX有两种形式；一种是在基本条件下发现的 许多细胞和组织，而另一种，COX-2，通常只表达 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，环氧合酶-2在腺瘤性息肉和结肠腺瘤中表达。 癌症，而这至少部分是由结构性的 抄写。这个项目的一个目标是定义 异常转录，并在另一个目的是探索假设 还有转录后调控。在第三个目标中，我们 将检测COX-2(或COX-1)在肠道中的过度表达 上皮足以引起息肉和癌症，如果是这样 与高脂肪饮食或存在其他突变的协同作用 常见于结肠癌(APC、P53)。 前列腺素合成酶促进结肠的机制 致癌机制尚不清楚--前列腺素可能会刺激细胞增殖 或抑制细胞凋亡。此外，这种酶(S)可以催化 外源物质的氧化，这可能具有类似的作用。最后， 由COX催化的反应可以产生诱变剂。我们将检查每一个 这些机制使用转基因小鼠、细胞系和人类组织，以及 从细胞生物学、分子生物学和 生物化学。 研究良好的廉价药物(非甾体抗炎药)可以 减少结肠息肉和癌症的发病率是令人兴奋的 化学预防的机会。这项建议旨在澄清 发生这种效应的机制，并应开辟新的方法来 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.