Identification and characterization of the functional role of miRNA in prostate c

前列腺癌中 miRNA 功能作用的鉴定和表征

• 批准号: 8292080
• 负责人: Ralph W. deVere White
• 金额: $ 27.89万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-09 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8292080
• 关键词: Ablation; Accounting; Address; American; Androgen Receptor; Androgens; Apoptosis; Applications Grants; Biological Markers; Biology; CDKN2A gene; Castration; Cell Cycle; Cell Proliferation; Cells; Cessation of life; Clinical; Data; Detection; Diagnosis; Disease; Disease Progression; Disease Resistance; Environment; Equipment; Event; Frequencies; Future; Genes; Goals; Growth; Human; Investigation; Knowledge; Life; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; MicroRNAs; Molecular; Nude Mice; Outcome; Patients; Play; Positioning Attribute; Prevention; Process; Prostate; Prostatic; Prostatic Neoplasms; Publishing; Puma; Receptor Signaling; Regulation; Research; Resistance; Role; Sampling; Serum; Small RNA; TP53 gene; Testing; Tissues; Tumor Suppressor Genes; Uncertainty; Work; cancer cell; effective therapy; innovation; insight; men; novel; outcome forecast; overexpression; prevent; public health relevance; research study; response; skills; therapeutic target; tumor; tumor xenograft; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): Our lack of understanding of the molecular events related to castrate-resistant (CR) growth of prostate cancer (CaP), results in the death of approximately 27,360 American men each year from this disease. The PI's long-term goal is to develop effective therapies for treating, or preferably preventing, the emergence of CR CaP. In this proposal, we will explore our recent discovery of aberrant expression of miR-125b in prostate cancer. Our hypothesis is that the expression of miR-125b in CR CaP cells is controlled by aberrantly-activated AR, that miR-125b facilitates CR growth of CaP cells by repressing the function of the p53 network, and that miR-125b has potential as a biomarker and a therapeutic target for the management of patients with CaP. Three specific Aims will be pursued to test this hypothesis. Aim 1 is to characterize the AR-mediated regulation of miR-125b in prostate cancer. We will confirm that AR signaling regulates miR-125b and determine whether overexpressed AR is aberrantly-activated in CR cells and subsequently upregulates miR-125b. These experiments will address the issue of why CR CaP cells and advanced CaP tumors express high levels of miR-125b. Aim 2 is to characterize the functions of miR-125b in prostate cancer. We will confirm that miR-125b stimulates tumorigenesis and CR growth by repressing the expression of p53, Puma, Bak1 and p14ARF, determine the role of miR-125b in anti-apoptosis and promoting cell proliferation, and evaluate the effects of miR-125b on the level and activity of AR. Data obtained from these proposed experiments will provide a mechanistic explanation of miR-125b-mediated prostatic tumorigenesis and CR growth. Aim 3 is to characterize miR-125b as a potential biomarker or therapeutic target for prostate cancer. We will detect the frequency of aberrantly-expressed miR-125b in clinical CaP samples and in sera from CaP patients and determine if miR-125b alters the response of CaP cells to therapy. These studies will facilitate the application of this miRNA as a biomarker for CaP diagnosis and prognosis and hopefully, as a target for CaP treatment. In summary, this proposal contains both technical and conceptual innovation, and has significant translational potential. Completion of these proposed studies should obtain valuable data and provide new insights into how CaP becomes castration-resistant. PUBLIC HEALTH RELEVANCE: Castration-resistant prostate cancer represents a major threat to the life of American men, resulting in the death of approximately 27,360 American men in 2009 from this disease. The main reason this disease has not been cured is lack of knowledge about the molecular alterations that occur in prostate cancer. In this grant application, we will explore our recent findings that prostate cancers highly express the microRNA miR-125b that is an endogenous small RNA and negatively regulates some tumor suppressor genes in human prostate cancer and other types of human cancer. We propose to investigate why prostate cancer cells aberrantly express miR-125b and how this microRNA promotes the growth of prostatic tumors in a castration environment. Completing these studies will not only provide new insights into the molecular alterations related to castration-resistant growth, it will also facilitate the application of this microRNA as a biomarker for diagnosis and as a target for treatment of this disease.

描述（由申请人提供）：我们对与前列腺癌（CAP）的抗性（CR）生长有关的分子事件缺乏了解，每年因这种疾病而死亡约27,360名美国男性。 PI的长期目标是开发有效治疗或最好防止CR CAP出现的疗法。在该提案中，我们将探讨我们最近发现miR-125b在前列腺癌中异常表达的发现。我们的假设是，miR-125b在Cr Cap细胞中的表达受到异常激活的AR的控制，MiR-125b通过抑制p53网络的功能来促进CR的CR生长，并且MiR-125b具有潜力作为生物标志物，并且是用于管理CAP患者的治疗靶标。将追求三个具体目标来检验这一假设。目的1是表征前列腺癌中AR介导的miR-125b调节。我们将确认AR信号传导调节miR-125b，并确定在CR细胞中是否异常激活AR并随后上调miR-125b。这些实验将解决为什么CR CAP细胞和晚期帽肿瘤表达高水平的miR-125b的问题。目的2是表征miR-125b在前列腺癌中的功能。我们将通过抑制p53，puma，bak1和p14arf的表达来确定miR-125b刺激肿瘤发生和CR生长，从而确定miR-125b在抗凋亡中的作用和促进细胞增殖，并评估mir-125b对mir-125b对AR的水平和活性的作用。从这些提出的实验获得的数据将提供MiR-125b介导的前列腺肿瘤发生和CR生长的机械解释。 AIM 3是将miR-125b表征为前列腺癌的潜在生物标志物或治疗靶标。我们将检测到临床上限样品中异常表达的miR-125b的频率和CAP患者的血清中的频率，并确定miR-125b是否改变了盖细胞对治疗的反应。这些研究将促进该miRNA作为CAP诊断和预后的生物标志物，并希望将其作为CAP处理的靶标。总而言之，该提案既包含技术和概念创新，并且具有巨大的翻译潜力。这些拟议的研究的完成应获得有价值的数据，并提供有关CAP如何变得cast割的新见解。 公共卫生相关性：耐cast割的前列腺癌代表着对美国男性生命的主要威胁，导致2009年因这种疾病而死亡约27,360名美国男性。这种疾病尚未治愈的主要原因是缺乏有关前列腺癌中发生的分子改变的知识。在此赠款应用中，我们将探讨我们最近的发现，即前列腺癌高度表达MicroRNA mir-125b，该mirORNA mir-125b是一种内源性小RNA，并对人类前列腺癌和其他类型的人类癌症中的一些肿瘤抑制基因进行负调节。我们建议研究为什么前列腺癌细胞异常表达miR-125b，以及该microRNA如何在cast割环境中促进前列腺肿瘤的生长。完成这些研究不仅将为与cast割抗性生长有关的分子改变提供新的见解，还将促进该microRNA作为诊断生物标志物的应用，并将其作为治疗该疾病的靶标。