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

描述（由申请人提供）：前列腺癌是美国男性癌症相关死亡的第二大原因。目前还没有生物标志物可以可靠地诊断或预测前列腺癌患者的疾病结局。识别晚期疾病（包膜外和转移性疾病）的生物标志物将为临床医生提供强大的作用，将不应被观察的男性从主动监测计划中排除，重要的是，识别那些需要转换为多模式治疗方案的侵袭性前列腺疾病的最高风险。microRNA（miRNAs）是一类在人类细胞生长和分化过程中起重要作用的非编码小分子RNA。miRNA在人类前列腺癌中经常错误表达，并有助于肿瘤形成和转移。然而，人们对miRNAs如何在前列腺中发挥作用以影响癌症进展为侵袭性、致命性疾病知之甚少。我们的申请将通过探索其作为基于流体的生物标志物和晚期囊外前列腺癌的治疗靶点，来表征miRNA（如miR-888簇）在促进前列腺癌进展中的作用。具体目标：我们将采用一种创新的生物标志物来源进行miRNA检测-尿中的前列腺分泌物（EPS尿）-在标准泌尿系统检查期间在临床上容易获得的非侵入性前列腺液。我们假设，在临床注释的EPS尿标本中鉴定的miRNA将与前列腺癌的潜在分子进展直接相关。事实上，我们的初步数据显示，miR- 888在高级别前列腺癌患者的EPS尿液中升高，并且可以在体外诱导人前列腺癌细胞的增殖和运动。在这个应用程序中，我们将1） 验证前列腺癌相关miRNAs（即miR-888簇成员）在大组EPS尿液样本中的优先表达（非癌症、器官局限性、非器官局限性和转移性疾病），并确定它们是否可以区分晚期和致命形式的前列腺癌;和2）使用体外测定和小鼠模型表征前列腺癌进展期间EPS尿衍生的miRNA（如miR-888）的功能作用。我们在进行这些研究方面处于独特的地位，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miRNA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.