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.
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