MicroRNAs in Advanced Prostate Cancer: A miR-21 model

晚期前列腺癌中的 MicroRNA：miR-21 模型

• 批准号: 8235056
• 负责人: SHAWN LUPOLD
• 金额: $ 33.01万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8235056
• 关键词: Accounting; Address; Advanced Development; American; Androgen Receptor; Apoptotic; Applications Grants; Area; Biological Assay; Cancer Model; Castration; Communities; Complementary DNA; Diagnosis; Disease; Disease Outcome; Distant Metastasis; Employee Strikes; Fluorescent in Situ Hybridization; Future; Gene Dosage; Gene Expression; Gene Expression Regulation; Genes; Goals; Growth; Health; Human; Immunohistochemistry; In Situ Hybridization; Knowledge; Light; Luciferases; Malignant Neoplasms; Malignant neoplasm of prostate; Maps; Mediating; MicroRNAs; Modeling; Neoplasm Metastasis; Oncogenes; Oncogenic; PC3 cell line; Pathway interactions; Patients; Post-Transcriptional Regulation; Primer Extension; Prognostic Marker; Promoter Regions; Prostate; Radical Prostatectomy; Recurrence; Regulation; Regulator Genes; Reporter; Research; Resistance; Role; Series; Signal Pathway; Small Interfering RNA; Specimen; Systemic Therapy; Terminal Disease; Testing; Tissue Microarray; Tissues; Transcript; United States; Western Blotting; advanced disease; human tissue; innovation; male; men; novel; outcome forecast; promoter; public health relevance; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): Advanced prostate cancer is an incurable and terminal disease which is characterized by metastasis and castration resistance. The mechanisms of progression to this advanced state are largely unknown. Our long term goal is to identify and characterize pathways which cause this lethal form of prostate cancer. We believe that novel discoveries in this focused area will have significantly impact on the prognosis and treatment of prostate cancer. MicroRNAs are a new class of regulatory molecules which control cellular pathways through post-transcriptional mechanisms. We have identified miR-21 as an Androgen-Receptor-regulated and oncogenic microRNA which is elevated in human prostate cancer. Importantly, miR-21 is sufficient to drive castration resistant tumor growth. In light of these discoveries, and the existing knowledge of miR-21 in other malignancies, we hypothesize that the miR-21 gene locus contributes to the development of advanced prostate cancer. The overall objective of this proposal are to (i) characterize the mechanisms of elevated miR-21 gene expression in human prostate cancer, (ii) to elucidate the pathways utilized by the miR-21 gene locus to promote cancer progression, and to compare miR-21 gene copy number and expression between human prostate cancers which have either been cured by primary therapy or recurred, progressed to metastasis, or castration resistance. PUBLIC HEALTH RELEVANCE: Prostate cancer (PCa) is a health problem of major significance in the United States. PCa strikes over 180,000 American men each year and accounts for approximately 10% of male cancer related deaths1. Despite an escalating research effort, there have been little to no advances in the treatment of metastatic and Castration Resistant Prostate Cancer (CRPC). Moreover, approximately 1/3rd of mean will recur following primary therapy2. Nonetheless, many men diagnosed with PCa will never develop the lethal or even symptomatic form of the disease within their lifetime3. Therefore, there are two major deficiencies in the current management of PCa: (1) Systemic Therapy - the lack of a successful therapy for CRPC and (2) Prognosis - the inability to consistently predict which cancers will progress. This grant application addresses these deficiencies by proposing studies of a novel pathway in CRPC and correlating genes in this pathway with disease recurrence and progression.

描述（申请人提供）：晚期前列腺癌是一种以转移和去势抵抗为特征的不治之症和终末期疾病。发展到这种高级状态的机制在很大程度上是未知的。我们的长期目标是确定和描述导致这种致命形式的前列腺癌的途径。我们相信这一领域的新发现将对前列腺癌的预后和治疗产生重大影响。microrna是一类通过转录后机制控制细胞通路的新型调控分子。我们已经确定miR-21是一种雄激素受体调控的致癌microRNA，在人类前列腺癌中升高。重要的是，miR-21足以驱动抗去势肿瘤生长。根据这些发现，以及对其他恶性肿瘤中miR-21的现有知识，我们假设miR-21基因位点有助于晚期前列腺癌的发展。本研究的总体目标是：(i)确定miR-21基因在人类前列腺癌中表达升高的机制，（ii）阐明miR-21基因位点促进癌症进展的途径，并比较miR-21基因拷贝数和表达在经初步治疗治愈或复发、进展到转移或去势抵抗的人类前列腺癌中的差异。