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: 8473050
• 负责人: Ralph W. deVere White
• 金额: $ 26.22万
• 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/8473050
• 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; castration resistant prostate cancer; effective therapy; innovation; insight; men; novel; outcome forecast; overexpression; prevent; prostate cancer cell; 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.

描述(由申请人提供)：我们对前列腺癌(CAP)的去势抵抗(CR)生长相关的分子事件缺乏了解，导致每年约27,360名美国男性死于这种疾病。PI的长期目标是开发有效的治疗方法来治疗或最好是预防CR帽的出现。在这项提案中，我们将探讨我们最近发现的miR-125b在前列腺癌中的异常表达。我们的假设是，miR-125b在CAP细胞中的表达受异常激活的AR控制，miR-125b通过抑制P53网络功能促进CAP细胞的CR生长，miR-125b有可能作为CAP患者治疗的生物标志物和治疗靶点。为了检验这一假设，我们将追求三个具体目标。目的1是研究AR介导的miR-125b在前列腺癌中的调节作用。我们将确认AR信号调节miR-125b，并确定在CR细胞中过度表达的AR是否异常激活，随后上调miR-125b。这些实验将解决为什么CR CAP细胞和晚期CAP肿瘤表达高水平miR-125b的问题。目的2研究miR-125b在前列腺癌中的作用。我们将证实miR-125b通过抑制p53、Puma、Bak1和p14ARF的表达来促进肿瘤的发生和CR的生长，确定miR-125b在抗细胞凋亡和促进细胞增殖中的作用，并评价miR-125b对AR水平和活性的影响。从这些拟议的实验中获得的数据将提供miR-125b介导的前列腺癌发生和CR生长的机制解释。目的3是鉴定miR-125b作为前列腺癌的潜在生物标志物或治疗靶点。我们将检测临床CAP样本和CAP患者血清中异常表达miR-125b的频率，并确定miR-125b是否改变CAP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的应用，并有望成为CAP治疗的靶点。总而言之，这项提议既有技术上的创新，也有概念上的创新，并具有巨大的翻译潜力。这些拟议研究的完成将获得有价值的数据，并为CAP如何抵抗阉割提供新的见解。

项目成果

Oncomir miR-125b suppresses p14(ARF) to modulate p53-dependent and p53-independent apoptosis in prostate cancer.

• DOI: 10.1371/journal.pone.0061064
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Amir S;Ma AH;Shi XB;Xue L;Kung HJ;Devere White RW
• 通讯作者: Devere White RW