MicroRNA dysregulation and bladder cancer prognosis

MicroRNA失调与膀胱癌预后

• 批准号: 8618961
• 负责人: Angeline Sanderson Andrew
• 金额: $ 24.66万
• 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 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8618961
• 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; 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; public health relevance; therapeutic target; transcriptome sequencing; tumor; tumorigenesis

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. !

7.项目总结/摘要 microRNA失调与膀胱癌预后膀胱癌是第四常见的 美国男性的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 复发性疾病在临床上最具挑战性的病例中，组织学检查显示 分化或原位癌特征（高级别Ta、T1或Tis）。其中一些患者经常 复发性肿瘤是治疗难治性的，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原发性肝癌中的预后标志物。 肿瘤组织。microRNA（miRNAs）是一种稳定的非蛋白质编码RNA分子， 在肿瘤发生过程中失调。以前没有针对尿路上皮癌的miRNA研究， 全面鉴定具有临床挑战性的非肌肉浸润性肿瘤中的预后miRNA 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， 复发、进展和生存数据来自一个大型流行病学队列，包括n=1062名非 肌肉浸润性尿路上皮细胞癌患者。我们首先计划鉴定与快速生长相关的miRNAs， 通过使用以下方法综合评估原发性肿瘤组织标本的miRNA表达水平， 小RNA序列计数分析（RNA-Seq）。我们将把我们的结果与来自 文献来优先考虑预后miRNAs。我们将在技术上确认优先的miRNA表达水平， 通过逆转录和实时定量PCR（qRT-PCR），并将评估miRNA在 尿路上皮癌细胞与其他细胞类型使用原位杂交。最后，我们将评估 使用我们的大规模研究， 基于人群的病例队列。成功鉴定一种预后失调的miRNA将有助于 通过早期发现快速复发和复发的膀胱癌， 难治性表型我们发现的失调的miRNAs也是潜在的可行的治疗靶点 并可能导致未来开发新的抗miR或miRNA替代疗法， 恶性肿瘤 !