Cyclooxygenase-2 and TGF-beta Interactions in Intestinal Neoplasia

（申请人描述）我们已经发现了TGF-betal诱导肠上皮细胞中COX-2表达的证据，并且对TGF-betal治疗的一些反应似乎依赖于COX-2。非转化肠上皮细胞的长期治疗导致生长抑制丧失，II型tgf - β受体下调，COX-2的组成性过表达，同时获得完全转化的致瘤表型。有几条实验证据表明COX-2和tgf - β信号的失调在肿瘤发生中很重要。我们观察到tgf - β 1和COX-2在人类结直肠肿瘤和结肠癌动物模型中的表达具有显著的一致性，并发现COX-2表达与tgf - β系统之间可能存在调节关系的证据。本项目的中心假设是COX-2和TGF-beta1之间存在重要的调节关系，肠上皮细胞转化形成一个正的自分泌环，COX-2和TGF-beta1均过表达，从而提高肿瘤细胞存活和肿瘤进展。该项目的长期目标是确定细胞转化过程中COX-2和tgf - β系统失调的机制，并确定结直肠癌化学预防和治疗的新分子靶点。中心假设将通过以下具体目标进行实验检验。具体目标确定tgf - β在肠细胞转化过程中是否调控COX-2的表达。具体目标2。确定RIE- tr细胞和ras -转化RIE细胞的转化表型是否依赖于COX-2的表达（和前列腺素的合成）。具体目标3。探讨tgf - β 1诱导COX-2的作用机制。

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.