Progranulin signaling in bladder cancer

膀胱癌中的颗粒体蛋白前体信号传导

• 批准号: 8521204
• 负责人: RENATO V. IOZZO
• 金额: $ 30.23万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8521204
• 关键词: Actin-Binding Protein; Anchorage-Independent Growth; Biological Markers; Biology; Bladder; Bladder Neoplasm; Bladder Urothelium; Calcium Signaling; Cancer Control; Cancer Model; Cell Adhesion; Cell Nucleus; Cessation of life; Complex; Cytoplasm; Diagnostic; Disease; Dominant-Negative Mutation; Focal Adhesion Kinase 1; Gene Proteins; Genomics; Goals; Growth; Growth Factor; Human; Laboratories; Lung; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Mediating; Membrane Proteins; Metastatic Neoplasm to the Lung; Modality; Molecular; Molecular and Cellular Biology; Neoplasm Metastasis; Neoplasms; Pathway interactions; Phenotype; Play; Primary Neoplasm; Prognostic Marker; Progranulin; Proteins; Proteomics; Regulation; Role; Scaffolding Protein; Series; Signal Pathway; Signal Transduction; Signaling Protein; Small Interfering RNA; Staging; Testing; Therapeutic Agents; Therapeutic Intervention; Time; Tissues; Translational Research; Tropism; Tumor Cell Invasion; United States; Urothelial Cell; Work; autocrine; base; cancer cell; cell motility; design; drebrins; in vivo; innovation; insight; migration; mouse model; mutant; neoplastic cell; novel; novel diagnostics; novel therapeutics; outcome forecast; overexpression; prognostic; research study; transcription factor; tumor; tumor progression; tumor xenograft

DESCRIPTION (provided by applicant): Bladder cancer is one of the most common cancer in the United States with 70,530 estimated cases and 14,680 estimated deaths in 2010. Regardless of the treatment modality, bladder cancer often recurs and metastasizes with very poor prognosis. Understanding the cellular and molecular mechanisms that regulate the biology of bladder cancer progression and invasion would be critical to develop new forms of treatments against this devastating disease. We have established that the growth factor progranulin plays a critical role in bladder cancer by regulating motility and invasion of malignant urothelial cells and demonstrated that progranulin acts as an autocrine growth factor. Moreover we have shown an increased expression of progranulin in invasive bladder tumors vis-¿-vis normal bladder. Collectively, our results support the hypothesis that progranulin may play a critical role as an autocrine growth factor in the establishment and progression of bladder cancer. Despite the strong connections with growth control and cancer, progranulin's mode of action is still poorly characterized. We have discovered that the focal adhesion kinase Pyk2 is activated by progranulin and its expression is increased in bladder cancer tissues. Conversely, knockdown of progranulin inhibits motility and anchorage-independent growth of metastatic bladder cancer cells. This indicates that progranulin may play a key role in the invasive (high motility) phenotype. Using pull-down experiments and proteomics we have identified for the first time drebrin as a membrane protein interacting with progranulin. Drebrin is an actin- binding protein involved in cell adhesion, motility and calcium signaling. Thus, we hypothesize that drebrin might be part of a supramolecular complex involved in progranulin signaling. We will test our hypothesis and accomplish the objectives of this application through the following specific aims: [1] Determine the mechanisms of progranulin action in bladder cancer cells. [2] Investigate the function of drebrin, a novel progranulin interacting protein, in the regulation of motility and invasion of bladder cancer cells. [3] Characterize the in vivo roles of progranulin, Pyk2 and drebrin in bladder cancer formation and progression. The expected results will provide not only novel information toward a better understanding of the mechanisms that regulate tumor cell motility but will also provide invaluable insight into the role of the progranulin signaling pathway in regulating the transition to the invasive phenotype in urothelial neoplasia. Once characterized the role of the progranulin pathway in bladder cancer formation and progression, these studies will greatly contribute to the identification of novel targets for therapeutic intervention in bladder tumors. In addition, progranulin, Pyk2 and drebrin may prove as novel diagnostic and/or prognostic biomarkers for bladder tumors.

描述（由适用提供）：膀胱癌是美国最常见的癌症之一，2010年估计为70,530例估计病例和14,680例估计死亡。无论治疗方式如何，膀胱癌通常会复发并转移，预后较差。了解调节膀胱癌进展和侵袭生物学的细胞和分子机制对于开发针对这种毁灭性疾病的新形式的治疗形式至关重要。我们已经确定，生长因子程序努力蛋白通过控制恶性尿路上皮细胞的运动性和侵袭在膀胱癌中起关键作用，并证明程序努尔蛋白起着自分泌生长因子的作用。此外，我们已经显示出在侵入性膀胱肿瘤中相对于正常膀胱的侵入性膀胱肿瘤的表达增加。总的来说，我们的结果支持以下假设：程序努菌素可能在膀胱癌的建立和发展中作为自分泌生长因子起关键作用。尽管与生长控制和癌症有密切的联系，但程序努力素的作用方式仍然很差。我们已经发现，局灶性激酶Pyk2被程序核蛋白激活，其表达在膀胱癌组织中增加。相反，敲低饮食蛋白抑制了转移性膀胱癌细胞的运动性和锚固无关的生长。这表明幼体蛋白可能在侵入性（高运动）表型中起关键作用。使用下拉实验和蛋白质组学，我们首次将DREBRIN鉴定为与前植物相互作用的膜蛋白。 DREBRIN是一种参与细胞粘附，运动性和钙信号传导的肌动蛋白结合蛋白。这是我们假设Drebrin可能是参与尿素信号传导的超分子复合物的一部分。我们将通过以下特定目的来检验我们的假设，并实现该应用的目标：[1]确定膀胱癌细胞中尿素作用的机制。 [2]研究了一种新型的尿素相互作用蛋白Drebrin在膀胱癌细胞的运动和侵袭中的功能。 [3]表征了体内生物素，pyk2和drebrin在膀胱癌的形成和进展中的作用。预期的结果不仅将提供新的信息，以更好地理解调节肿瘤细胞运动的机制，还将提供对尿皮细胞肿瘤中侵袭性表型的过渡到侵入性表型的作用的宝贵洞察力。一旦表征了尿素途径在膀胱癌形成和进展中的作用，这些研究将极大地有助于鉴定膀胱肿瘤治疗干预的新靶标。此外，幼虫，PYK2和DREBRIN可能被证明是膀胱肿瘤的新型诊断和/或预后生物标志物。