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.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 环氧合酶(COX)是前列腺素合成的关键酶，诱导型COX-2的过度表达参与了肿瘤和炎症综合征的发病过程。最近的数据表明，COX-2在结直肠癌的发生发展中起关键作用，并且COX-2的表达是肠上皮细胞癌变的限速步骤。越来越多的证据表明，COX-2基因调控的一个中心点是通过COX-2mRNA中存在的顺式作用元件在转录后水平进行的。这种富含AU的mRNA元件(ARE)存在于COX-2的3‘非翻译区(3’UTR)和许多与癌症相关的mRNAs中，通过与细胞RNA结合蛋白的相互作用，使它们的mRNAs迅速衰退。我们最近发现，RNA结合蛋白Hur在转录后水平上调节COX-2基因的表达，并证明COX-2在肿瘤中被异常诱导，部分原因是这种mRNA稳定因子的表达发生了变化。我们推测，Hur的过表达可能通过稳定COX-2和血管生成因子mRNAs来促进肠上皮细胞肿瘤的发生。这一中心假设将以下列具体目标加以阐述。 具体目标1：确定mRNA稳定因子HUR的表达改变是否可以促进肠道细胞转化和肿瘤发生。在目标1下，我们将确定Hur在促进肠上皮细胞COX-2表达方面的功能意义，并确定Hur介导的mRNA稳定对肠上皮细胞生长和致瘤性的生物学影响。 特定目的2：确定Hur在小鼠胃肠道中的过表达是否促进了COX-2的过表达和体内肿瘤的发生。利用转基因小鼠模型，概括了在人类结直肠癌细胞系和肿瘤中观察到的情况，我们将检验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上的COX-2等位基因的丢失。长期目标是了解转录后调控缺失促进结直肠癌COX-2表达的机制，并将HUR定义为治疗干预的新分子靶点。