MicroRNA dysregulation and bladder cancer prognosis

描述（由申请人提供）：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。超过一半的非肌肉侵袭性尿路上皮细胞癌患者会复发。临床上最具挑战性的病例是那些组织学表现为分化差或原位癌特征（高级别Ta、T1或Tis）的病例。其中一些患者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。本建议的目的是确定在原发肿瘤组织中这种快速复发表型的预后标志物。MicroRNAs （miRNAs）是稳定的非蛋白质编码RNA分子，在肿瘤发生过程中经常失调。之前没有关于尿路上皮癌的miRNA研究集中于全面鉴定具有临床挑战性的非肌肉侵袭性肿瘤类型的预后miRNA。我们收集了一个独特的基于人群的膀胱肿瘤组织库，其中包含了来自1062名非肌肉侵袭性尿路上皮细胞癌患者的广泛、长期复发、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的miRNA表达水平来鉴定与快速复发相关的miRNA。我们将把我们的结果与文献信息结合起来，优先考虑预后mirna。我们将通过反转录和定量实时PCR （qRT-PCR）技术确认miRNA的优先表达水平，并将使用原位杂交技术评估miRNA在尿路上皮癌细胞中与其他细胞类型的分布。最后，我们将使用基于人群的病例队列来评估优先miRNA与复发、进展和生存相关的预后价值。成功识别预后失调的miRNA将有助于通过早期发现快速复发和难治性表型来定制临床挑战性膀胱癌病例的管理。我们发现的失调的mirna也是潜在可行的治疗靶点，并可能导致未来针对这种恶性肿瘤开发新的抗mir或mirna替代疗法。

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.