Prostaglandin Receptor Regulation of Kidney Cancer

前列腺素受体对肾癌的调节

基本信息

批准号：
7758839
负责人：
Yehia Daaka
金额：
$ 30.4万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-11 至 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7758839
关键词：
Accounting Address Agonist American Animal Model Animals Arachidonic Acids Attenuated 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 Proteins 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 Research Role Signal Transduction Subcutaneous Injections Surface Tail Tertiary Protein Structure Tissues United States Veins 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 public health relevance receptor receptor expression research study tumor tumor initiation tumorigenic

Accounting Address Agonist American Animal Model Animals Arachidonic Acids Attenuated 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 Proteins 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 Research Role Signal Transduction Subcutaneous Injections Surface Tail Tertiary Protein Structure Tissues United States Veins 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 public health relevance receptor receptor expression research study tumor tumor initiation tumorigenic

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项目摘要

DESCRIPTION (provided by applicant): 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 1 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. PUBLIC HEALTH RELEVANCE: 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.

描述（由申请人提供）：肾细胞癌是癌症死亡的主要原因，其发病率在人口组中以每年2.5％的速度稳步增加。大约三分之一的患者患有转移性疾病，此类患者的预后较差，中位生存期为十个月。尽管手术对于治疗局部肾细胞癌（RCC）的治疗非常有效，但转移性疾病患者可用的治疗选择非常有限。因此，了解在RCC中运行的分子事件将有助于更好地了解癌症的分子发病机理，因此，为转移性疾病的高度特异性和有效的基于机制的治疗选择打开了大门。我们已经克隆了一条新的透明细胞RCC（RCC7），该系列是小鼠肿瘤和转移性的。 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 1 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.用PGE2治疗促进了RAP1介导的RCC7细胞侵袭，RAP1GAP的救出表达减弱了PGE2介导的细胞体外侵袭和动物的转移。基于这些结果并考虑到先前的知识，我们假设EP4的不受监管的表达/功能与RCC入侵有关。该应用的具体目的是：[1]使用可用的EP受体特异性激动剂和拮抗剂，以介导RCC细胞在体外介导的EP受体表达，并用RNAi敲低EP受体敲低，[2]来确定pGE2介导的RCC介导的rcc rccaul small gtpase ton to Proppase的分子机制，并[2] EP4和RAP1信号在使用动物模型系统的RCC肿瘤的体内生长和转移中的作用。这些研究的成功结论可能会确定EP4和RAP是有效治疗晚期肾脏恶性肿瘤的新药物靶标。公共卫生相关性：转移性肾细胞癌患者（RCC）的治疗方案有限，RCC的启动和进展涉及的机制尚不完全了解。我们已经将EP4和RAP确定为RCC细胞侵袭和转移的介体。 EP4信号传导和RAP失活的有针对性破坏可能会提供一个机会窗口，以干扰肾癌发展为目前无法治愈的晚期疾病。