The Role of Thromboxane A2 (TP) Receptor Beta in Bladder Cancer

血栓素 A2 (TP) 受体 Beta 在膀胱癌中的作用

• 批准号: 8240070
• 负责人: Omar Moussa
• 金额: $ 29.69万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8240070
• 关键词: Affect; Apoptotic; Biological Markers; Bladder; Cancer Cell Growth; Cancer Patient; Cancer cell line; Cell Line; Cell Proliferation; Cells; Characteristics; Clinical; Clinical Research; Complementary DNA; Complex; Coupled; Data; Development; Diagnostic; Diagnostic Neoplasm Staging; Disease Progression; Endothelial Cells; Epigenetic Process; Epithelial Cells; Excretory function; Exhibits; GTP-Binding Proteins; Genes; Genetic; Goals; Growth; Health; Human; In Vitro; Knowledge; Literature; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Mediator of activation protein; Molecular; Mutation; Neoplasm Metastasis; Nude Mice; Oncogenic; Outcome; PTEN Gene Inactivation; PTEN gene; Pathogenesis; Pathway interactions; Patients; Phenotype; Play; Probability; Process; Property; Protein Isoforms; Publishing; Receptor Activation; Receptor Signaling; Recurrence; Regulation; Research; Research Proposals; Role; Signal Pathway; Signal Transduction; Staging; Stream; Techniques; Therapeutic; Thromboxane A2; Thromboxane Receptor; Time; Tissues; Tumor Cell Invasion; Tumor Suppressor Proteins; Tumor stage; Urothelial Cell; Woman; autocrine; base; cancer cell; cell motility; design; in vivo; malignant phenotype; men; migration; mouse model; neoplastic cell; new therapeutic target; novel; outcome forecast; paracrine; pleiotrophin; prognostic; receptor; receptor expression; survivin; tumor; tumor growth; tumor progression; tumorigenesis; urinary

DESCRIPTION (provided by applicant): In the US, bladder cancer is the fourth most common cancer in men and the eighth most common cancer in women. Approximately 60,000 people develop bladder cancer each year. Unfortunately, recurrence, invasion, and metastasis, even after a seemingly successful treatment at a very early stage, are characteristic of bladder cancer. Studies directed towards elucidation of the factors involved in its progression should facilitate the design of molecularly based diagnostic and therapeutic approaches. Our preliminary data demonstrate that: (i) the thromboxane A2 (TP) beta receptor isoform uniquely is over-expressed in human bladder cancer and cell lines and over-expression is correlated with a poorer prognosis in patients; (ii) TP beta, but not TP alpha, receptor expression increases malignant phenotypes in vitro and produces a malignant transformation of immortalized bladder epithelial cells in vivo; (iii) TP receptor antagonists reduce bladder cancer cell growth, migration and invasion and inhibit tumor growth in vivo; and (iv) urinary TXB2 and TP beta receptor protein are significantly greater in bladder cancer patients compared to controls, supporting potential diagnostic and prognostic utility. Based upon our preliminary studies and published literature, we hypothesize that the increased expression of TP beta receptor and activation of its signaling pathways play a critical role in bladder cancer cell growth and metastases. To define the oncogenic potential of TP beta receptor signaling, we propose the following specific aims: 1: Determine the proximal mediators (G protein dependent and independent) of the signaling pathways coupled to the TP beta receptor isoform responsible for bladder cancer cell migration, invasion, and proliferation; 2. Determine the mechanism of the regulation by TP beta of the downstream effectors (tumor suppressor PTEN and pro-angiogenic pleiotrophin) responsible for its induced malignant phenotype and 3. Determine whether tissue expression of TXAS, TP beta receptor, urinary TXB2, urinary TP beta receptor, and down-stream effectors exhibit prognostic significance in the progression of human bladder cancer. The proposed studies utilize a combination of molecular and cellular techniques, mouse models when appropriate and clinical studies. These approaches provide a comprehensive analysis of possible tumor-related functions of TP beta receptor-signaling, and may identify a new therapeutic target for bladder cancer, and maybe other cancers. PUBLIC HEALTH RELEVANCE: Data presented in this research proposal indicate for the first time the association between thromboxane receptor 2 isoform expression and poor survival in bladder cancer patients. There is a strong probability that the proposed research will advance our knowledge in bladder cancer and there is a potential possibility that we can predict the disease progression from superficial to invasive based on the levels of thromboxane receptor 2 isoform and/or its down-stream effectors.

描述（由申请人提供）：在美国，膀胱癌是男性第四大常见癌症，女性第八大常见癌症。每年约有60，000人患膀胱癌。不幸的是，即使在非常早期阶段看似成功的治疗之后，复发、侵袭和转移也是膀胱癌的特征。针对阐明其进展中所涉及的因素的研究应有助于设计基于分子的诊断和治疗方法。我们的初步数据表明：（i）血栓素A2（TP）β受体亚型在人膀胱癌和细胞系中独特地过表达，并且过表达与患者的较差预后相关;（ii）TP β而不是TP α受体表达在体外增加恶性表型，并且在体内产生永生化膀胱上皮细胞的恶性转化;（iii）TP受体拮抗剂减少膀胱癌细胞生长、迁移和侵袭并抑制体内肿瘤生长;和（iv）膀胱癌患者的尿TXB 2和TP β受体蛋白与对照相比显著更高，支持潜在的诊断和预后效用。基于我们的初步研究和已发表的文献，我们假设TP β受体的表达增加及其信号通路的激活在膀胱癌细胞生长和转移中起关键作用。为了确定TP β受体信号传导的致癌潜力，我们提出了以下具体目标：1：确定与负责膀胱癌细胞迁移、侵袭和增殖的TP β受体亚型偶联的信号传导途径的近端介质（G蛋白依赖性和非依赖性）; 2.确定TP β对下游效应物（肿瘤抑制因子PTEN和促血管生成多效因子）的调节机制，所述下游效应物负责其诱导的恶性表型; 3.确定TXAS、TP β受体、尿TXB 2、尿TP β受体和下游效应物的组织表达在人膀胱癌进展中是否具有预后意义。拟定研究采用分子和细胞技术、小鼠模型（如适用）和临床研究的组合。这些方法提供了对TP β受体信号传导可能的肿瘤相关功能的全面分析，并可能为膀胱癌甚至其他癌症确定新的治疗靶点。公共卫生相关性：本研究提案中的数据首次表明了血栓素受体2亚型表达与膀胱癌患者生存不良之间的相关性。有一个很大的可能性，拟议的研究将推进我们在膀胱癌的知识，有一个潜在的可能性，我们可以预测疾病的进展，从浅表到浸润性的基础上血栓素受体2亚型和/或其下游效应物的水平。