MicroRNA dysregulation and bladder cancer prognosis

描述(申请人提供)：microRNA失调与膀胱癌预后。膀胱癌是美国男性第四大常见恶性肿瘤。超过一半的非肌肉浸润性尿路上皮细胞癌患者经历了复发。在临床上最具挑战性的病例是那些组织学表现为低分化或原位癌特征的病例(高级别Ta、T1或Tis)。这些患者中有一些经常复发的肿瘤难以治疗，但很难预测哪些患者具有这种表型。这项建议的目的是在原发肿瘤组织中确定这种快速复发表型的预后标志物。MicroRNAs(MiRNAs)是一种稳定的、非蛋白质编码的RNA分子，在肿瘤发生过程中经常受到失调。以前还没有关于尿路上皮癌的miRNA研究集中于全面识别具有临床挑战性的非肌肉浸润性肿瘤类型中影响预后的miRNAs。我们已经建立了一个独特的基于人群的膀胱肿瘤组织库，该组织库包含来自n=1062名非肌肉浸润性尿路上皮细胞癌患者的大规模流行病学队列中广泛的、长期的复发、进展和生存数据。我们首先计划通过使用小RNA序列计数分析(RNA-Seq)全面评估原发肿瘤组织标本中miRNA的表达水平来确定与快速复发相关的miRNAs。我们将把我们的结果与文献中的信息结合起来，以确定预测miRNAs的优先顺序。我们将通过逆转录和实时定量聚合酶链式反应(qRT-PCR)从技术上确定miRNA的优先表达水平，并将通过原位杂交来评估miRNA在尿路上皮癌细胞中的分布。最后，我们将使用我们的大型基于人群的病例队列来评估优先的miRNA与复发、进展和生存相关的预后价值。成功识别预后异常的miRNA将有助于通过早期检测快速复发和难治性表型来量身定做具有临床挑战性的膀胱癌病例的治疗。我们发现的失调miRNAs也是潜在的可行治疗靶点，并可能导致未来针对这种恶性肿瘤的新型抗miR或miRNA替代疗法的发展。

DESCRIPTION (provided by applicant): MicroRNA dysregulation and bladder cancer prognosis. Bladder cancer is the fourth most common malignancy in U.S. men. More than half of non-muscle invasive urothelial cell carcinoma patients experience recurrent disease. Among the most clinically challenging cases are those with histologies that denote poor differentiation or carcinoma in situ features (high grade Ta, T1, or Tis). Some of these patients have frequently recurring tumors that are refractory to treatment, but it is difficult to predict which patients hae this phenotype. The objective of this proposal is to identify prognostic markers of this rapidly recurrent phenotype in the primary tumor tissue. MicroRNAs (miRNAs) are stable, non-protein coding RNA molecules that are frequently dysregulated during tumorigenesis. No previous miRNA studies in urothelial carcinoma have focused on comprehensively identifying prognostic miRNAs within the clinically challenging, non-muscle invasive tumor types. We have assembled a unique population-based tissue bank of bladder tumors with extensive, long-term recurrence, progression, and survival data from a large epidemiologic cohort encompassing n=1062 non-muscle invasive urothelial cell carcinoma patients. We first plan to identify the miRNAs associated with rapid recurrence by comprehensively assessing primary tumor tissue specimens for miRNA expression levels using small RNA sequence count analysis (RNA-Seq). We will integrate our results with information from the literature to prioritize the prognostic miRNAs. We will technically confirm the priority miRNA expression levels by reverse-transcription and quantitative real-time PCR (qRT-PCR), and will evaluate the miRNA distribution in urothelial carcinoma cells versus other cell-types using in situ hybridization. Finally, we will evaluate the prognostic value of the prioritized miRNA in relation to recurrence, progression and survival using our large population-based case cohort. Successful identification of a prognostic dysregulated miRNA will help tailor management of clinically challenging bladder cancer cases by enabling early detection of rapidly recurrent and refractory phenotypes. The dysregulated miRNAs that we identify are also potentially viable therapeutic targets and could lead to the future development of novel anti-miR or miRNA-replacement therapies for this malignancy.