MicroRNA dysregulation and bladder cancer prognosis

MicroRNA失调与膀胱癌预后

• 批准号: 8787723
• 负责人: Angeline Sanderson Andrew
• 金额: $ 14.09万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8787723
• 关键词: Binding; Biological Assay; Bladder; Bladder Neoplasm; Cancer Prognosis; Carcinoma; Carcinoma in Situ; Cells; Cessation of life; Clinical; Clinical Management; Clinical Trials; Code; Data; Development; Disease; Early Diagnosis; Epidemiologic Studies; Epidemiology; Future; Gene Expression Regulation; Gene Targeting; Half-Life; Health; Histologic; Histology; In Situ Hybridization; Intravesical Instillation; Lead; Length; Literature; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Messenger RNA; Methods; MicroRNAs; Molecular; Oncogenes; Organ; Outcome; Patients; Phenotype; Play; Prevalence; Primary Neoplasm; Prognostic Marker; Proliferating; Proteins; RNA; RNA Sequences; Recurrence; Recurrent disease; Refractory; Replacement Therapy; Reverse Transcription; Role; Site; Slide; Small RNA; Specimen; Staging; Subgroup; Testing; Time; Tissue Banking; Tissue Banks; Transitional Cell Carcinoma; Translational Research; Tumor Markers; Tumor Suppressor Proteins; Tumor Tissue; Urothelial Cell; Work; base; cell type; cohort; experience; follow-up; gene therapy; high risk; men; molecular marker; mortality; new therapeutic target; novel; patient population; population based; prognostic; prognostic value; therapeutic target; transcriptome sequencing; tumor; tumorigenesis

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.

描述（由申请人提供）：MicroRNA失调和膀胱癌预后。膀胱癌是美国男性中第四大常见的恶性肿瘤。超过一半的非肌层浸润性尿路上皮细胞癌患者会复发。其中最具临床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。这些患者中有些经常复发，对治疗无效，但很难预测哪些患者具有这种表型。该建议的目的是确定原发肿瘤组织中这种快速复发表型的预后标志物。微小RNA（miRNAs）是稳定的非蛋白质编码RNA分子，其在肿瘤发生期间经常失调。以前在尿路上皮癌中没有miRNA研究集中在全面鉴定临床上具有挑战性的非肌肉浸润性肿瘤类型中的预后miRNA。我们收集了一个独特的基于人群的膀胱肿瘤组织库，该组织库具有广泛的长期复发、进展和生存数据，这些数据来自一个大型流行病学队列，包括n=1062例非肌层浸润性尿路上皮细胞癌患者。我们首先计划通过使用小RNA序列计数分析（RNA-Seq）全面评估原发性肿瘤组织标本的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中的信息结合起来，优先考虑预后miRNAs。我们将通过逆转录和实时定量PCR（qRT-PCR）技术确认优先miRNA表达水平，并将使用原位杂交评估尿路上皮癌细胞与其他细胞类型中的miRNA分布。最后，我们将使用我们的大规模基于人群的病例队列，评估优先miRNA与复发、进展和生存相关的预后价值。成功鉴定预后失调的miRNA将有助于通过早期检测快速复发和难治性表型来定制具有临床挑战性的膀胱癌病例的管理。我们发现的失调的miRNAs也是潜在的可行的治疗靶点，并可能导致未来开发针对这种恶性肿瘤的新型抗miR或miRNAs替代疗法。