Prostaglandin Receptor Regulation of Kidney Cancer

前列腺素受体对肾癌的调节

• 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
• 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

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，其发病率在人群中以每年2.5%的速度稳步增加。大约三分之一的患者存在转移性疾病，并且这些患者的预后很差，中位生存期为10个月。虽然手术对于治疗局限性肾细胞癌（RCC）非常有效，但转移性疾病患者的治疗选择非常有限。因此，了解RCC中的分子事件将有助于更好地了解癌症的分子发病机制，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方案打开了大门。我们克隆了一个新的透明细胞RCC（RCC 7）系，它在小鼠中具有致瘤性和转移性。基因和蛋白质表达分析显示，RCC 7细胞具有改变的G蛋白偶联受体信号传导中间体的水平，包括增加的1亚基的Gs和Gq，和EP 4亚型的前列腺素E2（PGE 2）受体的表达，和减少的小GTP酶失活剂Rap 1GAP的表达，与正常的上皮肾细胞相比。PGE 2处理促进Rap 1介导的RCC 7细胞侵袭，Rap 1GAP的拯救表达减弱PGE 2介导的细胞体外侵袭和动物转移。基于这些结果，并考虑到以前的知识，我们假设，不受调节的表达/功能的EP 4参与肾细胞癌的侵袭。本申请的具体目的是：[1]使用可用的EP受体特异性激动剂和拮抗剂以及用RNAi敲低EP受体来分析EP受体表达并建立介导RCC细胞体外侵袭的EP亚型，[2]为了确定负责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活化，以及[3]使用动物模型系统确定EP 4和Rap 1信号传导在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将EP 4和Rap确定为有效治疗晚期肾脏恶性肿瘤的新型药物靶点。 公共卫生相关性：转移性肾细胞癌（RCC）患者的治疗选择有限，并且RCC发生和进展的机制尚不完全清楚。我们已经确定EP 4和Rap是RCC细胞侵袭和转移的介质。有针对性地破坏EP 4信号传导和Rap失活可能提供一个机会窗口，以干扰肾癌进展为目前无法治愈的晚期疾病。