权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
8433453
负责人：
Yehia Daaka
金额：
$ 27.48万
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 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8433453
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 Targeting 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

项目摘要

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.

摘要肾癌的前列腺素受体调节肾细胞癌是癌症死亡的主要原因，并且其发病率在2010年稳步增加。各人口群体的年增长率为2.5%。大约三分之一的患者患有转移性疾病，并且此类患者的预后差，中位生存期为10个月。尽管手术治疗局部肾细胞癌（RCC）非常有效，可用于转移性疾病患者的治疗选择非常有限。因此，我们认为，了解RCC中的分子活动将有助于更好地了解癌症的分子发病机制，因此，打开大门，高度特异性和有效的转移性疾病的机制为基础的治疗选择。我们克隆了一个新的透明细胞系 RCC（RCC 7），其在小鼠中具有致瘤性和转移性。基因和蛋白质表达分析揭示了RCC 7细胞具有改变的G蛋白偶联受体信号传导水平，中间体，包括增加表达的？Gs和Gq亚基，以及前列腺素E2（PGE 2）受体，并降低小GT3失活剂的表达 Rap 1GAP，与正常肾上皮细胞相比。PGE 2治疗促进了 Rap 1介导的RCC 7细胞侵袭，Rap 1GAP的拯救表达减弱了PGE 2- 介导的细胞体外侵袭和动物中的转移。根据这些结果，并考虑到考虑到先前的知识，我们假设EP 4的不受调节的表达/功能是参与RCC侵袭。本申请的具体目的是：[1]分析EP受体表达，并建立介导RCC细胞体外侵袭的EP亚型。可用的EP受体特异性激动剂和拮抗剂，以及用RNAi敲低EP受体，[2] 为了确定PGE 2介导的RCC细胞侵袭的分子机制，特别强调小GT受体Rap 1的激活，以及[3]确定EP 4和Rap 1的作用使用动物模型系统在RCC肿瘤的体内生长和转移中的信号传导。的这些研究的成功结论可能会将EP 4和Rap确定为有效的新药物靶点，晚期肾脏恶性肿瘤的治疗叙述：转移性肾细胞癌（RCC）患者的治疗选择有限，参与RCC的启动和进展的基因尚不完全清楚。我们已经确定EP 4和Rap为 RCC细胞侵袭和转移的介质。靶向破坏EP 4信号传导和失活 Rap可能提供一个机会窗口，以干扰肾癌的进展，无法治愈的晚期疾病

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Rap1GAP regulates renal cell carcinoma invasion.

DOI：
10.1016/j.canlet.2012.01.022
发表时间：
2012-07-01
期刊：
CANCER LETTERS
影响因子：
9.7
作者：
Kim, Wan-Ju;Gersey, Zachary;Daaka, Yehia
通讯作者：
Daaka, Yehia

Expansion of CCR8(+) inflammatory myeloid cells in cancer patients with urothelial and renal carcinomas.

DOI：
10.1158/1078-0432.ccr-12-2091
发表时间：
2013-04-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
0
作者：
Eruslanov E;Stoffs T;Kim WJ;Daurkin I;Gilbert SM;Su LM;Vieweg J;Daaka Y;Kusmartsev S
通讯作者：
Kusmartsev S

S-nitrosylation-regulated GPCR signaling.