Role of the EPS Urine-Derived MicroRNA miR-888 in Prostate Cancer Progression

描述(申请人提供)：前列腺癌是美国男性癌症相关死亡的第二大原因。目前还不存在可靠诊断或预测前列腺癌患者疾病结局的生物标记物。识别晚期疾病(囊外和转移性疾病)的生物标志物将为临床医生发挥强大的作用，将不应被观察的男性排除在主动监测计划之外，重要的是，识别那些需要切换到多模式治疗方案的侵袭性前列腺癌的最高风险人群。MicroRNAs(MiRNAs)是一种小的非编码RNA，在控制人类细胞的生长和分化方面发挥着重要作用。MiRNAs经常在人类前列腺癌中错误表达，并与肿瘤的形成和转移有关。然而，人们对miRNAs在前列腺中如何发挥作用影响癌症进展为侵袭性、致命性疾病的作用知之甚少。我们的应用将通过探索miRNAs作为晚期囊外前列腺癌的液体生物标记物和治疗靶点，来表征miRNAs在促进前列腺癌进展中的作用。具体目标：我们将使用一种创新的生物标记物来源来检测miRNA-尿中表达的前列腺液(EPS尿液)-在临床上很容易在标准泌尿学检查中非侵入性获得的前列腺液。我们假设，在临床注释的EPS尿样中发现的miRNAs将直接与前列腺癌的潜在分子进展相关。事实上，我们的初步数据显示，高级别前列腺癌患者的EPS尿液中miR-888水平升高，并可在体外诱导人前列腺癌细胞的增殖和运动。在此应用程序中，我们将1) 2)通过实时荧光定量聚合酶链式反应分析，验证一大批前列腺癌相关miRNAs(即miR-888簇的成员)在EPS尿液样本(非癌、器官受限、非器官受限和转移疾病)中的表达，并确定它们是否可以区分晚期和致命的前列腺癌；以及2)使用体外分析和小鼠模型研究EPS尿源性miRNAs，如miR-888，在前列腺癌进展过程中的功能作用。我们处于进行这些研究的独特位置，因为我们的翻译团队可以访问全国最大的EPS尿液储存库之一。研究EPS尿源性miRNAs在前列腺癌进展中的作用有望揭示检测和治疗这种致命疾病的新策略。

DESCRIPTION (provided by applicant): Prostate cancer is the second leading cause of cancer-related deaths among men in the United States. No biomarkers exist that reliably diagnoses or predict disease outcome in prostate cancer patients. Identification of a biomarker for advanced disease (extracapsular and metastatic disease) would serve a powerful role for clinicians in excluding men from Active Surveillance Programs who should not be observed and importantly, identifying those at highest risk for aggressive prostate disease that require a switc to multimodal treatment regimens. MicroRNAs (miRNAs) are small non-coding RNAs that play essential roles in controlling growth and differentiation in human cells. MiRNAs are often misexpressed in human prostate cancers and contribute to tumor formation and metastasis. However, it is poorly understood how miRNAs function in the prostate to influence cancer progression to aggressive, lethal disease. Our application will characterize the role of miRNAs, such as the miR-888 cluster, in promoting prostate cancer progression by exploring their use as fluid-based biomarkers and therapeutic targets for advanced forms of extracapsular prostate cancer. SPECIFIC AIMS: We will employ an innovative biomarker source for miRNA detection - expressed prostatic secretions in urine (EPS urine) - prostatic fluids that are easily obtained non-invasively in the clinic during a standard urological exam. We hypothesize that miRNAs identified in clinically annotated EPS urine specimens will directly correlate with the underlying molecular progression of prostate cancer. Indeed, our preliminary data shows that miR- 888 is elevated in EPS urine from patients with high-grade prostate cancer and can function to induce proliferation and motility of human prostate cancer cells in vitro. In this application, we will 1) validate the expression of prioritized prostate cancer-associated miRNAs, namely members of the miR-888 cluster, within a large cohort of EPS urine specimens (non-cancer, organ-confined, non-organ confined & metastatic disease) via quantitative real-time PCR analysis and determine if they can discriminate for advanced and lethal forms of prostate cancer; and 2) characterize the functional role of EPS urine- derived miRNAs, such as miR-888, during prostate cancer progression using in vitro assays and mouse models. We are in a unique position to conduct these studies since our translational group has access to one of the largest EPS urine repositories in the nation. Investigating the role of EPS urine-derived miRNAs during prostate cancer progression promises to reveal novel strategies to detect and treat this deadly disease.