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

EPS 尿液来源的 MicroRNA miR-888 在前列腺癌进展中的作用

• 批准号: 8883426
• 负责人: Aurora Esquela Kerscher
• 金额: $ 16.52万
• 依托单位: EASTERN VIRGINIA MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8883426
• 关键词: 3' Untranslated Regions; Advisory Committees; African American; Age; Animal Model; Binding; Biological Markers; Cancer Etiology; Cancer Patient; Castration; Cell Proliferation; Cells; Cessation of life; Clinic; Clinical; Combined Modality Therapy; Data; Detection; Diagnosis; Diagnostic; Differentiation and Growth; Disease; Disease Outcome; Disseminated Malignant Neoplasm; Early treatment; Epithelial Cells; Etiology; Extracapsular; Gene Expression; Health; Human; In Vitro; Incidence; Individual; Lead; Life Expectancy; Liquid substance; Malignant Neoplasms; Malignant neoplasm of prostate; Massage; Messenger RNA; MicroRNAs; Molecular; Mus; Neoplasm Metastasis; Oncogenic; Organ; Outcome; Pathway interactions; Patients; Pilot Projects; Play; Population; Positioning Attribute; Preventive; Process; Property; Prostate; Prostate-Specific Antigen; Prostatic; Prostatic Diseases; Prostatic Neoplasms; Proteins; RNA Degradation; Regulator Genes; Resistance; Risk; Role; Sampling; Services; Source; Specimen; Surveillance Program; Testing; Time; Tissues; Translations; Treatment Protocols; Treatment outcome; United States; Untranslated RNA; Urethra; Urine; Work; Xenograft procedure; advanced disease; base; cell motility; cohort; differential expression; digital; follow-up; high risk; improved; in vitro Assay; innovation; member; men; miRNA expression profiling; migration; mouse model; novel; novel diagnostics; novel strategies; novel therapeutics; prostate cancer cell; prostate cancer cell line; rectal; repository; research study; screening; therapeutic target; tool; tumor; tumor progression; tumorigenesis; urologic

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.

描述（由申请人提供）：前列腺癌是美国男性与癌症相关死亡的第二大原因。没有生物标志物可靠地诊断或预测前列腺癌患者的疾病结果。鉴定晚期疾病的生物标志物（囊外和转移性疾病）将对临床医生排除不应被观察到的主动监测计划中的男性发挥强大的作用，并重要地确定那些对侵略性前列腺疾病的风险最高的人，而前列腺疾病的风险最高，而前列腺疾病需要SWITC对多二型治疗方案。 microRNA（miRNA）是小型非编码RNA，在控制人类细胞的生长和分化中起着至关重要的作用。 miRNA通常在人类前列腺癌中受到重视，并有助于肿瘤形成和转移。然而，鲜为人知的是，miRNA在前列腺中的功能如何影响癌症发展为侵略性致命疾病。我们的应用将表征miRNA（例如miR-888簇）在促进前列腺癌进展中的作用，通过探索其用作基于液体的生物标志物的用途和用于先进形式的囊外前列腺癌的治疗靶标。具体目的：我们将使用创新的生物标志物来源来进行miRNA检测 - 在标准泌尿外科检查期间在诊所中轻松获得尿液（EPS尿液）的前列腺分泌（EPS尿液） - 前列腺液。我们假设在临床注释的EPS尿液标本中鉴定出的miRNA将直接与前列腺癌的基本分子进展有关。确实，我们的初步数据表明，高级前列腺癌患者的EPS尿液中miR-888升高，并且可以在体外诱导人前列腺癌细胞的增殖和运动性。在此应用程序中，我们将1） 验证优先前列腺癌相关的miRNA的表达，即miR-888群集的成员，在大量EPS尿液标本中（非癌症，器官限制，非器官，非Organ和转移性疾病）通过定量的实时PCR分析，并通过定量的实时PCR分析，并确定是否可以区分先进和LETH的特定癌症癌症； 2）表征使用体外测定和小鼠模型在前列腺癌进展过程中EPS尿液衍生的miRNA（例如miR-888）的功能作用。我们处于独特的地位来进行这些研究，因为我们的翻译小组可以使用美国最大的EPS尿液存储库之一。研究EPS尿液衍生的miRNA在前列腺癌进展过程中的作用有望揭示发现和治疗这种致命疾病的新型策略。

项目成果

Characterization and Evidence of the miR-888 Cluster as a Novel Cancer Network in Prostate.

• DOI: 10.1158/1541-7786.mcr-17-0321
• 发表时间: 2018-04
• 期刊: Molecular cancer research : MCR
• 作者: Hasegawa T;Glavich GJ;Pahuski M;Short A;Semmes OJ;Yang L;Galkin V;Drake R;Esquela-Kerscher A
• 通讯作者: Esquela-Kerscher A