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

描述(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6万人罹患膀胱癌。不幸的是，复发、侵袭和转移是膀胱癌的特征，即使在非常早期的治疗似乎是成功的。旨在阐明其进展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膀胱癌细胞系中唯一的过度表达，并且与患者的不良预后相关；(Ii)TPβ受体在体外的表达增加了膀胱癌的恶性表型，并在体内导致永生化的膀胱上皮细胞的恶性转化；(Iii)TP受体拮抗剂能够抑制膀胱癌细胞的生长、迁移和侵袭，并在体内抑制肿瘤的生长；(Iv)与对照组相比，膀胱癌患者尿液中TXB2和TPβ受体蛋白的表达显著增加，从而支持潜在的诊断和预后价值。根据我们的初步研究和已发表的文献，我们假设TPβ受体的表达增加及其信号通路的激活在膀胱癌细胞的生长和转移中起着关键作用。为了明确TPβ受体信号通路的致癌潜能，我们提出了以下特定目标：1.确定与TPβ受体亚型偶联的信号通路的近端介体(G蛋白依赖和非依赖性)，负责膀胱癌细胞的迁移、侵袭和增殖；2.确定TPβ调控下游效应分子(抑癌基因PTEN和促血管生成因子)的机制；3.确定TxAs、TPβ受体、尿液TXB2、尿液TPβ受体和下游效应分子的组织表达在膀胱癌进展中是否具有预后意义。拟议的研究结合了分子和细胞技术、适当的小鼠模型和临床研究。这些方法提供了对TPβ受体信号通路可能的肿瘤相关功能的全面分析，并可能确定膀胱癌或其他癌症的新治疗靶点。公共卫生相关性：这项研究提案中提出的数据首次表明，血栓素2受体2亚型的表达与膀胱癌患者的低生存率之间存在关联。这项拟议的研究极有可能促进我们对膀胱癌的认识，并有可能根据血栓素2受体2亚型和/或其下游效应物的水平来预测疾病从浅表到侵袭的进展。

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.