MicroRNA dysregulation and bladder cancer prognosis

7.项目摘要/摘要 MicroRNA异常与膀胱癌预后的关系膀胱癌是最常见的第四种癌症 美国男性的恶性疾病。超过一半的非肌肉浸润性尿路上皮细胞癌患者经历 复发性疾病。在临床上最具挑战性的病例中，那些组织学表现为 分化或原位癌特征(高级别Ta、T1或Tis)。其中一些患者经常 难以治疗的复发性肿瘤，但很难预测哪些患者具有这种表型。 这项建议的目的是确定这种快速复发的表型在初发期的预后标志。 肿瘤组织。MicroRNAs(MiRNAs)是一种稳定的、非蛋白质编码的RNA分子，通常 在肿瘤发生过程中调节失调。以前对尿路上皮癌的miRNA研究还没有集中在 全面识别临床上具有挑战性的非肌肉浸润性肿瘤中的预后miRNAs 类型。我们已经建立了一个独特的基于人群的膀胱肿瘤组织库，具有广泛的、长期的 来自一个大型流行病学队列的复发、进展和生存数据，该队列包括1062例非 肌肉浸润性尿路上皮细胞癌患者。我们首先计划确定与Rapid相关的miRNA 综合评估原发肿瘤组织标本miRNA表达水平的复发 小RNA序列计数分析(RNA-Seq)。我们将把我们的结果与来自 文献以确定预测miRNAs的优先顺序。我们将从技术上确认miRNA的优先表达水平 通过逆转录和实时定量聚合酶链式反应(qRT-PCR)，评价miRNA在 用原位杂交法比较尿路上皮癌细胞与其他细胞类型。最后，我们将评估 使用我们的大样本，优先的miRNA与复发、进展和生存的关系的预后价值 以人口为基础的病例队列。成功识别预后异常的miRNA将有助于定制 通过能够及早发现快速复发的和具有临床挑战性的膀胱癌病例 难治性表型。我们发现的失调的miRNAs也是潜在的治疗靶点。 并可能导致未来针对这一问题的新型抗miR或miRNA替代疗法的开发 恶毒。 好了！

7. PROJECT SUMMARY/ABSTRACT 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 have 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. !