MicroRNAs in Advanced Prostate Cancer: A miR-21 model

描述（由申请人提供）：晚期前列腺癌是一种无法治愈的晚期疾病，其特征是转移和去势抵抗。进展到这种晚期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表征导致这种致命形式的前列腺癌的途径。我们相信，在这一重点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节的致癌microRNA，在人前列腺癌中升高。重要的是，miR-21足以驱动去势抵抗性肿瘤生长。根据这些发现，以及miR-21在其他恶性肿瘤中的现有知识，我们假设miR-21基因位点有助于晚期前列腺癌的发展。本提案的总体目标是（i）表征人前列腺癌中miR-21基因表达升高的机制，（ii）阐明miR-21基因座用于促进癌症进展的途径，并比较通过初级治疗治愈或复发、进展为转移的人前列腺癌之间的miR-21基因拷贝数和表达，或去势抵抗。 前列腺癌（PCa）是美国一个重要的健康问题。PCa每年侵袭超过180，000名美国男性，占男性癌症相关死亡的约10%。尽管研究工作不断升级，但转移性和去势抵抗性前列腺癌（CRPC）的治疗进展甚微。此外，初次治疗后约1/3的平均值会复发2。尽管如此，许多被诊断患有前列腺癌的男性在其一生中永远不会发展出致命的甚至是有症状的疾病。因此，目前PCa的管理存在两个主要缺陷：（1）全身治疗-缺乏CRPC的成功治疗，以及（2）预后-无法一致地预测哪些癌症将进展。这项拨款申请通过提出CRPC中新途径的研究以及该途径中与疾病复发和进展相关的基因来解决这些缺陷。

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.