REGULATION OF COX-2 EXPRESSION IN INTESTINAL NEOPLASIA

肠肿瘤中 COX-2 表达的调节

• 批准号: 7720813
• 负责人: DAN ALAN DIXON
• 金额: $ 17.72万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7720813
• 关键词: 3' Untranslated Regions; Address; Alleles; Angiogenic Factor; Be++ element; Beryllium; Biological; Colorectal; Colorectal Cancer; Computer Retrieval of Information on Scientific Projects Database; Data; Development; Enzymes; Epithelial Cells; Funding; Gastrointestinal tract structure; Gene Expression; Gene Expression Regulation; Goals; Grant; Human; Inflammatory; Institution; Intestinal Neoplasms; Intestines; Malignant Neoplasms; Mediating; Messenger RNA; Molecular Target; Mus; Pathogenesis; Post-Transcriptional Regulation; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Protein Overexpression; RNA-Binding Proteins; Rate; Regulation; Research; Research Personnel; Resources; Role; Source; Syndrome; Therapeutic Intervention; Transgenic Organisms; Tumor Cell Line; Tumorigenicity; United States National Institutes of Health; carcinogenesis; cell growth; cell transformation; cis acting element; cyclooxygenase 1; cyclooxygenase 2; in vivo; mRNA Decay; mRNA Expression; mRNA Stability; mouse model; tumor; tumorigenesis

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cyclooxygenases (COX) are key enzymes in prostaglandin synthesis and overexpression of inducible COX-2 has been shown to participate in pathogenesis of cancer and inflammatory syndromes. Recent data strongly associates the critical role of COX-2 in colorectal cancer development and implicate COX-2 expression as a rate-limiting step in intestinal epithelial cell carcinogenesis. Growing evidence indicates a central point of COX-2 gene regulation occurs at the post-transcriptional level through cis-acting elements present in the COX-2 mRNA. This AU-rich mRNA element (ARE) is present in the 3' untranslated region (3'UTR) of COX-2 and many cancer-associated mRNAs and targets them for rapid mRNA decay through interaction with cellular RNA-binding proteins. We have recently shown that the RNA binding protein HuR regulates COX-2 gene expression on a post-transcriptional level and demonstrated that COX-2 is aberrantly induced in tumors due in part to altered expression of this mRNA stability factor. We hypothesize that overexpression of HuR promotes intestinal epithelial cell tumorigenesis through stabilization of COX-2 and angiogenic factor mRNAs. This central hypothesis will be addressed with the following specific aims. Specific Aim 1: Determine if altered expression of the mRNA-stability factor HuR can promote intestinal cell transformation and tumorigenesis. Under Aim 1 we will determine the functional significance HuR has in promoting COX-2 expression in intestinal epithelial cells and determine the biological impact HuR-mediated mRNA stabilization has upon epithelial cell growth and tumorigenicity. Specific Aim 2: Determine if HuR overexpression in the murine gastrointestinal tract promotes COX-2 overexpression and tumorigenesis in vivo. Utilizing a transgenic mouse model, which recapitulates what is observed in human colorectal cell lines and tumors, we will examine the ability of HuR to promote COX-2 overexpression and intestinal tumorigenesis. Furthermore, we will determine if HuR-mediated mRNA stabilization can compensate for loss of a functional COX-2 allele. The long-term goal is to understand the mechanism by which loss of post-transcriptional regulation promotes COX-2 expression in colorectal cancer and define HuR as a new molecular target for therapeutic intervention.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 环氧酶（COX）是前列腺素合成中的关键酶，并且已显示可诱导的COX-2的过表达参与癌症和炎性综合征的发病机理。最近的数据将COX-2在结直肠癌发育中的关键作用密切相关，并将COX-2表达视为肠上皮细胞癌发生的速率限制步骤。越来越多的证据表明，COX-2基因调节的中心点是通过COX-2 mRNA中的顺式作用元素在转录后水平发生。这种富含Au的mRNA元素（IS）存在于COX-2的3'未翻译区（3'UTR）和许多与癌症相关的mRNA中，并通过与细胞RNA结合蛋白相互作用而靶向它们以快速mRNA衰变。我们最近表明，RNA结合蛋白HUR在转录后水平上调节COX-2基因表达，并证明COX-2在肿瘤中异常诱导，部分原因是该mRNA稳定性因子的表达改变。我们假设HUR的过表达通过稳定COX-2和血管生成因子mRNA促进肠上皮细胞肿瘤发生。该中心假设将以以下特定目的解决。 具体目标1：确定mRNA稳定性因子HUR的表达是否改变可以促进肠细胞转化和肿瘤发生。在AIM 1下，我们将确定HUR在促进肠上皮细胞中COX-2表达的功能意义，并确定HUR介导的MRNA稳定化对上皮细胞生长和肿瘤性的生物学影响。 具体目标2：确定鼠胃肠道中的HUR过表达是否会促进COX-2的过表达和体内肿瘤发生。利用转基因小鼠模型，该模型概括了人类结直肠细胞系和肿瘤中观察到的内容，我们将研究HUR促进COX-2过表达和肠道肿瘤发生的能力。此外，我们将确定HUR介导的mRNA稳定是否可以补偿功能性COX-2等位基因的损失。长期目标是了解转录后调节损失促进结直肠癌中COX-2表达的机制，并将HUR定义为治疗干预的新分子靶标。