Prostaglandin Receptor Regulation of Kidney Cancer

摘要 前列腺素受体对肾癌的调节 肾细胞癌是癌症死亡的主要原因，其发病率在 各人口群体的年增长率为2.5%。在场的患者中约有三分之一患有 转移性疾病，此类患者预后较差，中位生存期为10个月。 虽然手术对治疗局限性肾细胞癌(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， 了解RCC中运行的分子事件将有助于更好地洞察 癌症的分子发病机制，因此，打开了高度特异和有效的大门 转移性疾病的基于机制的治疗选择。我们已经克隆了一种新的透明细胞系 肾细胞癌(RCC7)是在小鼠体内发生和转移的肿瘤。基因和蛋白质表达分析 发现RCC7细胞的G蛋白偶联受体信号水平发生了变化 中间体，包括表达增强的？Gs和Gq亚基和EP4亚型 前列腺素E_2(PGE_2)受体和小GTP酶失活因子表达降低 Rap1GAP，与正常肾上皮细胞比较。前列腺素E_2治疗可促进 Rap1介导的RCC7细胞侵袭和Rap1GAP的挽救表达减弱PGE2- 介导细胞体外侵袭和动物体内转移。基于这些结果，并考虑到 考虑到先前的知识，我们假设EP4的未调控表达/功能是 参与了RCC的入侵。该应用的具体目的是：[1]分析EP受体 表达并建立介导肾癌细胞体外侵袭的EP亚型(S) 可用的EP受体特异性激动剂和拮抗剂，以及用RNAi击倒EP受体，[2] 探讨前列腺素E_2介导的肾癌细胞侵袭的分子机制 特别强调小GTP酶Rap1的激活，以及确定Ep4和Rap1的作用 用动物模型系统研究肾癌肿瘤体内生长和转移中的信号转导。这个 这些研究的成功结束可能会确定EP4和Rap是有效的新药物靶点 晚期肾脏恶性肿瘤的治疗。叙述： 转移性肾细胞癌(RCC)的治疗选择和机制有限 目前对肾细胞癌的发生、发展过程尚不完全清楚。我们已经确认EP4和Rap是 肾癌细胞侵袭和转移的介质。靶向干扰EP4信号转导和失活 Rap的表达可能为干预肾癌的进展提供了一扇机会之窗 无法治愈的晚期疾病。

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.