Cyclooxygenase-2 and TGF-beta Interactions in Intestinal Neoplasia

产品说明：（申请人的描述）我们已经发现了TGF-β 1诱导肠上皮细胞中考克斯-2表达的证据，并且对TGF-β 1治疗的一些应答似乎依赖于考克斯-2。 长期治疗未转化的肠上皮细胞导致生长抑制丧失，II型TGF-β受体下调，考克斯-2组成性过表达，沿着获得完全转化的肿瘤发生表型。 有几条实验证据表明，考克斯-2和TGF-β信号转导的失调在肿瘤发生中是重要的。 我们已经观察到TGF-β 1和考克斯-2在人类结直肠肿瘤和结肠致癌物动物模型中表达的显著一致性，并且已经开发出证据表明考克斯-2表达和TGF-β系统之间可能存在调节关系。 该项目的中心假设是考克斯-2和TGF-β 1之间存在重要的调节关系，肠上皮细胞转化导致考克斯-2和TGF-β 1过表达的阳性自分泌环，从而导致肿瘤细胞存活和肿瘤进展增强。 该项目的长期目标是确定细胞转化过程中考克斯-2和TGF-β系统失调的机制，并确定用于结肠直肠癌化学预防和治疗的新分子靶点。 中心假设将通过实验进行检验，具体目标如下。具体目标1。 为了确定TGF-β是否调节 考克斯-2在肠细胞转化过程中的作用。具体目标2。 为了确定RIE-Tr的转化表型是否 细胞和Ras转化的RIE细胞依赖于考克斯-2 表达（和前列腺素合成）。具体目标3。 为了确定诱导考克斯-2的机制， TGF-β 1。

DESCRIPTION: (Applicant's Description) We have developed evidence that TGF-betal induces the expression of COX-2 in intestinal epithelial cells, and that some of the responses to TGF-betal treatment appear to be dependent on COX-2. Long-term treatment of nontransformed intestinal epithelial cells results in loss of growth inhibition, downregulation of the type II TGF-beta receptor, and constitutive overexpression of COX-2, along with the acquisition of a fully transformed tumorigenic phenotype. There are several lines of experimental evidence to suggest that dysregulation of both COX-2 and TGF-beta signaling are important in tumorigenesis. We have observed remarkable concordance of expression of both TGF-beta1 and COX-2 in human colorectal tumors and in animal models of colon carcinogens and have developed evidence that there may be a regulatory relationship between COX-2 expression and the TGF-beta system. The central hypothesis for this project is that there is an important regulatory relationship between COX-2 and TGF-beta1, and that intestinal epithelial cell transformation results in a positive autocrine loop with overexpression of both COX-2 and TGF-beta1 resulting in enhanced tumor cell survival and tumor progression. The long-term goal of this project is to identify the mechanisms involved in the dysregulation of the COX-2 and TGF-beta systems during cell transformation and to identify novel molecular targets for chemoprevention and therapy of colorectal carcinoma. The central hypothesis will be tested experimentally with the following specific aims. Specific Aim 1. To determine whether TGF-beta regulates the expression of COX-2 during intestinal cell transformation. Specific Aim 2. To determine whether the transformed phenotype of the RIE-Tr cells and Ras-transformed RIE cells is dependent upon COX-2 expression (and prostaglandin synthesis). Specific Aim 3. To determine the mechanism of induction of COX-2 by TGF-beta1.