COBRE: USC: REGULATION OF COX-2 IN INTESTINAL NEOPLASIA

COBRE：USC：COX-2 在肠肿瘤中的调节

• 批准号: 7381898
• 负责人: DAN ALAN DIXON
• 金额: $ 15.08万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7381898
• 关键词: COBRE; USC; REGULATION; COX; INTESTINAL

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. Overexpression of the prostaglandin synthase COX-2 plays a critical role in colorectal cancer and associated inflammatory diseases. A central point of COX-2 gene regulation occurs at the post-transcriptional level through AU-rich mRNA elements (AREs). The ARE is common feature among cancer-associated genes and targets them for rapid mRNA decay through interaction with RNA-binding proteins. We have identified that the mRNA stability factor HuR to be aberrantly overexpressed in tumors and promotes loss of post-transcriptional regulation through mRNA stabilization. We hypothesize that overexpression of HuR promotes intestinal epithelial cell tumorigenesis through stabilization of COX-2 and angiogenic factor mRNAs. Normally expressed at low levels and located in the nucleus, HuR cytoplasmic overexpression was observed in human tissues obtained from ulcerative colitis, colon adenomas, adenocarcinomas, and metastases. Overexpression of the HuR target gene COX-2 colocalized with elevated HuR expression. To determine the functional significance of HuR overexpression in vivo, a HuR-transgenic mouse (HuR-Tg) was created to overexpress HuR in GI epithelium. HuR-Tg mice display normal growth and breeding characteristics without any morphological changes in the GI tract of the HuR-Tg mice, however elevated endogenous COX-2 and VEGF mRNA were observed in the GI tract. The impact of HuR overexpression on tumorigenesis was examined through breeding with the APCMin/+ mouse. HuR-Tg/APCMin/+lines display approximately 2-fold increased tumor burden in both the colon and small intestine compared to APCMin/+control. These findings indicate HuR promotes tumorigenesis downstream of a tumor-initiating event and identify this mRNA stability factor as a new molecular target for controlling pathogenic gene expression.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。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。列出的机构适用于该中心，这不一定是调查员的机构。前列腺素合酶COX-2的过表达在结直肠癌和相关炎症性疾病中起关键作用。 COX-2基因调节的中心点通过富含AU的mRNA元素（ARES）发生在转录后水平上。这是与癌症相关基因的常见特征，并通过与RNA结合蛋白相互作用来靶向它们以快速mRNA衰减。我们已经确定，mRNA稳定性因子HUR在肿瘤中异常过表达，并通过mRNA稳定来促进转录后调节的丧失。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。 通常以低水平表达并位于核中，在从溃疡性结肠炎，结肠腺瘤，腺癌和转移的人体组织中观察到HUR细胞质过表达。 HUR靶基因COX-2的过表达与HUR表达升高共定位。为了确定HUR过表达体内的功能意义，创建了HUR-转基因小鼠（HUR-TG），以过表达GI上皮的HUR。 HUR-TG小鼠表现出正常的生长和繁殖特征，而HUR-TG小鼠的GI道没有任何形态学变化，但是在GI区域中观察到内源性COX-2和VEGF mRNA升高。通过使用APCMIN/+小鼠繁殖，检查了HUR过表达对肿瘤发生的影响。与APCMIN/+对照相比，HUR-TG/APCMIN/+线在结肠和小肠中显示出大约2倍的肿瘤负担。这些发现表明，HUR促进了肿瘤发射事件的下游肿瘤发生，并将该mRNA稳定性因子确定为控制致病基因表达的新分子靶标。