REGULATION OF COX-2 EXPRESSION IN INTESTINAL NEOPLASIA

肠肿瘤中 COX-2 表达的调节

• 批准号: 7959759
• 负责人: DAN ALAN DIXON
• 金额: $ 13.32万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7959759
• 关键词: 3' Untranslated Regions; Address; Alleles; Angiogenic Factor; Be++ element; Beryllium; Biological; Colon Carcinoma; 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; RNA-Binding Proteins; Regulation; Research; Research Personnel; Resources; Role; Source; Syndrome; Therapeutic Intervention; Transgenic Mice; Tumor Cell Line; Tumorigenicity; United States National Institutes of Health; anticancer research; carcinogenesis; cell growth; cell transformation; cis acting element; cyclooxygenase 2; in vivo; mRNA Decay; mRNA Stability; mouse model; overexpression; 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.

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 环氧合酶（考克斯）是前列腺素合成的关键酶，诱导型考克斯-2的过度表达参与了癌症和炎症综合征的发病机制。最近的数据强烈关联的关键作用，考克斯-2在结直肠癌的发展和牵连考克斯-2的表达作为一个限速步骤，在肠上皮细胞癌变。越来越多的证据表明，考克斯-2基因调控的中心点是通过考克斯-2 mRNA中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）存在于考克斯-2和许多癌症相关mRNA的3'非翻译区（3' UTR）中，并通过与细胞RNA结合蛋白的相互作用靶向它们以使mRNA快速衰减。我们最近发现，RNA结合蛋白HuR在转录后水平调节考克斯-2基因表达，并证明考克斯-2在肿瘤中被异常诱导，部分原因是这种mRNA稳定因子的表达改变。我们推测HuR的过度表达通过稳定考克斯-2和血管生成因子mRNA促进肠上皮细胞肿瘤的发生。这一中心假设将通过以下具体目标加以解决。 具体目标1：确定mRNA稳定性因子HuR的表达改变是否可以促进肠细胞转化和肿瘤发生。在目标1下，我们将确定HuR在促进肠上皮细胞中考克斯-2表达方面的功能意义，并确定HuR介导的mRNA稳定对上皮细胞生长和致瘤性的生物学影响。 具体目标2：确定小鼠胃肠道中HuR过表达是否促进体内考克斯-2过表达和肿瘤发生。利用转基因小鼠模型，它概括了在人类结直肠细胞系和肿瘤中观察到的情况，我们将研究HuR促进考克斯-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考克斯-2等位基因的丧失。长期目标是了解转录后调节的丧失促进结直肠癌中考克斯-2表达的机制，并将HuR定义为治疗干预的新分子靶点。