Cyclooxygenase-2 and TGF-beta Interactions in Intestinal Neoplasia

描述：(申请人描述)我们已经发现了转化生长因子-β1诱导肠上皮细胞环氧合酶-2表达的证据，并且对转化生长因子-β1治疗的一些反应似乎依赖于环氧合酶-2。长期治疗未转化的肠上皮细胞会导致生长抑制丧失，II型转化生长因子-β受体下调，COX-2结构性过表达，并获得完全转化的致瘤表型。有几条实验证据表明，环氧合酶-2和转化生长因子-β信号的失调在肿瘤的发生中起重要作用。我们观察到转化生长因子-β1和环氧合酶-2在人类大肠肿瘤和结肠癌致癌动物模型中的表达具有显著的一致性，并发现环氧合酶-2的表达与转化生长因子-β系统之间可能存在调控关系。该项目的中心假设是，COX-2和转化生长因子-β1之间存在重要的调控关系，肠上皮细胞转化导致一个正的自分泌循环，COX-2和转化生长因子-β1过表达，从而提高肿瘤细胞的存活率和肿瘤进展。该项目的长期目标是确定细胞转化过程中环氧合酶-2和转化生长因子-β系统调控失调的机制，并为结直肠癌的化学预防和治疗寻找新的分子靶点。中心假设将通过实验进行验证，具体目标如下。具体目的1.探讨转化生长因子-β在肠道细胞转化过程中对环氧合酶-2表达的调节作用。具体目的2.确定RIE-Tr细胞和RAS转化的RIE细胞的转化表型是否依赖于COX-2的表达(以及前列腺素的合成)。具体目的3.探讨转化生长因子-β1诱导环氧合酶-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.