Identification of Genes Involved in Bladder Cancer

膀胱癌相关基因的鉴定

• 批准号: 7211280
• 负责人: JOHN L CLIFFORD
• 金额: $ 12.58万
• 依托单位: LOUISIANA STATE UNIV HSC SHREVEPORT
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-25 至 2008-08-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7211280
• 关键词: bladder neoplasm; genes; human; urinary bladder epithelium

DESCRIPTION (provided by applicant): Project Summary: Transitional cell carcinoma of the bladder (TCC) ranks 4th in incidence of all cancers in the developed world, yet the mechanisms of its origin and progression remain poorly understood. There are also few useful diagnostic or prognostic biomarkers for this disease. The long-term aim of this proposal is to determine molecular mechanisms involved in early and late steps in the development of TCC. In addition we hope to identify new biomarkers for detection, diagnosis and prognosis of TCC. To accomplish this we will use a mouse model for bladder cancer in which the SV40 large T antigen (SV40 T) is expressed under the control of the uroplakin promoter, which restricts expression to the bladder urothelium. These mice (UPII- SV40T) develop TCC, which is preceded by a condition resembling human CIS. The hypothesis underlying this proposal is that there are differences in gene expression profiles and gene regulatory networks between invasive TCC and CIS and between CIS and distant normal appearing urothelium, and that these changes are indicative of the malignant state. This hypothesis is based on the multistep carcinogenesis concept. An extension of our hypothesis is that CIS is an intermediate step between normal urothelium and invasive TCC and that there should be changes in gene expression corresponding to this intermediate state. The specific aims are: 1. Identify the genes and gene regulatory networks that are differentially expressed between the normal urothelium of nontransgenic and UPII-SV40T mice, CIS and TCC, using Affymetrix GeneChip(r) Arrays. The relevence of individual genes to human TCC will be validated by assessing expression of the human homologs in patient TCC and normal urothelium specimens. In silico analysis of the microarray data, which includes generating gene expression profiles (clustering analysis) and the development of promoter models based on the promoter sequences of the differentially expressed genes will be performed. 2. Assess the function and potential relevance to bladder carcinogenesis of these genes in vivo by stable overexpression, or siRNA-mediated suppression, of the validated genes in human bladder-derived cell lines. Relevence: Completion of these studies should advance our understanding of the molecular events underlying TCC development. In addition, the identification of genes differentially expressed between normal urothelium, CIS and TCC will provide much needed diagnostic and prognostic markers for this disease.

项目概述：膀胱移行细胞癌（TCC）在发达国家的所有癌症发病率中排名第四，但其起源和进展机制仍知之甚少。对于这种疾病也很少有有用的诊断或预后生物标志物。本提案的长期目标是确定参与TCC发展早期和后期步骤的分子机制。此外，我们希望找到新的TCC检测、诊断和预后的生物标志物。为了实现这一点，我们将使用膀胱癌小鼠模型，其中SV40大T抗原（SV40 T）在uroplakin启动子的控制下表达，该启动子将表达限制在膀胱尿路上皮。这些小鼠（UPII- SV40T）发展为TCC，在此之前会出现类似于人类CIS的病症。这一建议的假设是，在侵袭性TCC和CIS之间，以及CIS和远处正常尿路上皮之间，基因表达谱和基因调控网络存在差异，这些变化预示着恶性状态。这一假设是基于多步骤癌变的概念。我们的假设的延伸是CIS是正常尿路上皮和侵袭性TCC之间的中间步骤，并且应该存在与此中间状态相对应的基因表达变化。具体目标是：1。使用Affymetrix基因芯片(r)阵列鉴定非转基因和UPII-SV40T小鼠、CIS和TCC正常尿路上皮之间差异表达的基因和基因调控网络。个体基因与人类TCC的相关性将通过评估患者TCC和正常尿路上皮标本中人类同源物的表达来验证。将对微阵列数据进行计算机分析，包括生成基因表达谱（聚类分析）和基于差异表达基因的启动子序列开发启动子模型。2. 通过在人膀胱源性细胞系中稳定过表达或sirna介导的抑制，评估这些基因在体内的功能及其与膀胱癌发生的潜在相关性。相关性：这些研究的完成将促进我们对TCC发展的分子事件的理解。此外，鉴定正常尿路上皮、CIS和TCC之间差异表达的基因将为该疾病提供急需的诊断和预后标记。