MicroRNAs in Advanced Prostate Cancer: A miR-21 model

描述(申请人提供)：晚期前列腺癌是一种无法治愈的晚期疾病，其特点是转移和去势抵抗。进展到这种高级状态的机制在很大程度上是未知的。我们的长期目标是识别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。MicroRNAs是一类新的调控分子，通过转录后机制控制细胞通路。我们已经确定miR-21是一种受雄激素受体调节的致癌microRNA，在人类前列腺癌中升高。重要的是，miR-21足以推动抗去势肿瘤的生长。根据这些发现，以及对miR-21在其他恶性肿瘤中的现有知识，我们假设miR-21基因座与晚期前列腺癌的发展有关。本研究的总体目标是：(1)阐明miR-21基因在前列腺癌中表达升高的机制；(2)阐明miR-21基因座促进肿瘤进展的途径；比较经初治治愈、复发、进展为转移或去势抵抗的前列腺癌之间miR-21基因拷贝数和表达的差异。

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.