Prostaglandin Receptor Regulation of Kidney Cancer

前列腺素受体对肾癌的调节

• 批准号: 8239456
• 负责人: Yehia Daaka
• 金额: $ 28.32万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-11 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8239456
• 关键词: Accounting; Address; Agonist; American; Animal Model; Animals; Arachidonic Acids; Attenuated; Basic Science; Binding; Biological Models; Biopsy; Cancer Etiology; Cause of Death; Cell Line; Cells; Cellular Morphology; Cessation of life; Clear Cell; Clinical Research; Cyclic AMP; Data; Deletion Mutation; Diagnosis; Dinoprostone; Disease; Distal; Drug Delivery Systems; Enzymes; Event; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; GTPase-Activating Proteins; Gene Expression; Growth; Guanine; Guanine Nucleotide Exchange Factors; Guanosine Triphosphate; Heart Diseases; Human; Hydrolysis; Implant; In Vitro; Incidence; Kidney; Knowledge; Lead; Link; Lung; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Mediator of activation protein; Metastatic Renal Cell Cancer; Molecular; Monomeric GTP-Binding Proteins; Mus; Mutation; Names; Neoplasm Metastasis; Nude Mice; Operative Surgical Procedures; Organ; Outcome; Pathogenesis; Pathologic; Patients; Population Group; Prostaglandin Receptor; Prostaglandins; Proteins; RNA Interference; Regulation; Renal Cell Carcinoma; Renal carcinoma; Role; Signal Transduction; Subcutaneous Injections; Surface; Tail; Tertiary Protein Structure; Tissues; United States; Veins; abstracting; advanced disease; base; cancer initiation; capsule; cell motility; cyclooxygenase 2; effective therapy; human WFDC2 protein; implantation; in vivo; in vivo Model; insight; kidney epithelial cell; lymph nodes; new therapeutic target; novel; outcome forecast; prevent; protein expression; receptor; receptor expression; research study; tumor; tumor initiation; tumor progression; tumorigenic

ABSTRACT PROSTAGLANDIN RECEPTOR REGULATION OF KIDNEY CANCER Renal cell carcinoma is a leading cause of cancer death, and its incidence is steadily increasing at an annual rate of 2.5% across population groups. Approximately one third of patients present with metastatic disease, and the prognosis of such patients is poor with a median survival of ten months. Although surgery is highly effective for the treatment of localized renal cell carcinoma (RCC), treatment options available for patients with metastatic disease are very limited. Hence, understanding the molecular events operating in RCC will help in gaining better insight into the molecular pathogenesis of the cancer and, therefore, open the door to highly specific and effective mechanism-based treatment options for metastatic disease. We have cloned a new line of clear cell RCC (RCC7) that is tumorigenic and metastatic in mice. Gene and protein expression analyses revealed that the RCC7 cells possess altered levels of G protein-coupled receptor signaling intermediates, including increased expression of the ? subunits of Gs and Gq, and EP4 subtype of prostaglandin E2 (PGE2) receptor, and decreased expression of the small GTPase inactivator Rap1GAP, in comparison to normal epithelial kidney cells. Treatment with PGE2 promoted the Rap1-mediated RCC7 cell invasion, and the rescued expression of Rap1GAP attenuated the PGE2- mediated cell invasion in vitro and metastasis in animals. Based on these results, and taking into account previous knowledge, we hypothesize that unregulated expression/function of the EP4 is involved in RCC invasion. The specific aims of this application are: [1] To profile EP receptors expression and to establish the EP subtype(s) that mediate the RCC cell invasion in vitro using available EP receptor-specific agonists and antagonists, and EP receptor knockdown with RNAi, [2] To determine the molecular mechanisms responsible for the PGE2-mediated RCC cell invasion with special emphasis on small GTPase Rap1 activation, and [3] To determine the role of EP4 and Rap1 signaling in the in vivo growth and metastasis of RCC tumors using animal model systems. The successful conclusion of these studies may identify EP4 and Rap as novel drug targets effective for the treatment of advanced kidney malignancies. Narrative: Patients with metastatic renal cell carcinoma (RCC) have limited treatment options, and mechanisms involved in the initiation and progression of RCC are not fully known. We have identified EP4 and Rap as mediators of invasion and metastasis of RCC cells. Targeted disruption of EP4 signaling and inactivation of Rap may provide a window of opportunity to interfere with progression of kidney cancer to currently incurable advanced disease.

摘要