Oncogenic Function of ATDC in Bladder Cancer

ATDC 在膀胱癌中的致癌功能

• 批准号: 9491077
• 负责人: DIANE M SIMEONE
• 金额: $ 48.58万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-10 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9491077
• 关键词: Ataxia-Telangiectasia Group D Complementing; Binding; Biological Models; Biology; Bladder; Bladder Neoplasm; Bladder Urothelium; DNA Damage; DNA Methylation; DNMT3a; Data; Development; Disease; Event; Gene Expression Profiling; Human; Human Cell Line; Inflammation; Lead; Malignant neoplasm of urinary bladder; Mediating; Methylation; Molecular; Neoplasm Metastasis; Oncogenes; Oncogenic; Organ; PTEN gene; Penetrance; Phenotype; Prognostic Marker; RB1 gene; Radiation; Resistance; Role; Sampling; Signal Transduction; TP53 gene; Therapeutic; Tissues; Transgenic Mice; Transgenic Model; Tumor Suppressor Genes; Up-Regulation; Urothelium; beta catenin; cancer initiation; cancer invasiveness; cancer risk; chemotherapy; cytotoxic; gene complementation; improved; mouse model; new therapeutic target; novel; overexpression; promoter; public health relevance; response; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Bladder cancer is a common and deadly disease, but the molecular events leading to its development are incompletely understood. We have recently identified a novel oncogene, Ataxia-Telangiectasia Group D Complementing (ATDC), which drives initiation and progression of bladder tumors in transgenic mice. These tumors are indistinguishable from their human counterparts. ATDC expression is elevated (about 70%) in human invasive bladder cancers and correlates with poorer survival after chemotherapy. In other tumor types, ATDC binds p53, modulates DNA damage responses and up-regulates beta-catenin signaling. In preliminary data, we find that ATDC expression is induced by inflammation, associated with decreased expression of PTEN and RB1, two important tumor suppressor genes implicated in bladder tumorigenesis, and show that ATDC promotes methylation and silencing of the PTEN promoter through upregulation of DNMT3a. We hypothesize that ATDC is a crucial determinant of formation, progression and the cytotoxic response in bladder cancer. To better understand the role of ATDC in bladder cancer, we propose the following studies: AIM 1: To characterize the role of ATDC in bladder cancer initiation, progression and metastasis using novel transgenic mouse models and determine the role of inflammation in inducing ATDC expression in normal urothelium. AIM 2: To characterize the role of PTEN, RB1 and p53 in ATDC-mediated bladder tumor formation and progression using both human and mouse model systems. AIM 3: To determine if ATDC expression in bladder cancer drives progression to invasive disease. AIM 4: To determine if ATDC expression promotes bladder tumor resistance to chemotherapy. These studies will characterize a novel mechanism of bladder tumor development and a valuable transgenic model of bladder cancer. We will also use existing human cell lines and primary human tumor samples to elucidate the molecular mechanisms by which ATDC induces bladder cancer and mediates resistance to chemotherapy. These studies are significant because understanding ATDC's oncogenic activity in bladder cancer may lead to new prognostic biomarkers and improved therapeutic approaches in humans.

描述（由申请人提供）：膀胱癌是一种常见且致命的疾病，但导致其发生的分子事件尚不完全清楚。我们最近发现了一种新的癌基因，共济失调毛细血管扩张 D 组互补 (ATDC)，它驱动转基因小鼠膀胱肿瘤的发生和进展。这些肿瘤与人类肿瘤没有区别。 ATDC 表达在人类浸润性膀胱癌中升高（约 70%），并且与化疗后较差的生存率相关。在其他肿瘤类型中，ATDC 结合 p53，调节 DNA 损伤反应并上调 β-连环蛋白信号传导。在初步数据中，我们发现 ATDC 表达是由炎症诱导的，与 PTEN 和 RB1（与膀胱肿瘤发生有关的两个重要抑癌基因）表达下降有关，并表明 ATDC 通过上调 DNMT3a 促进 PTEN 启动子的甲基化和沉默。我们假设 ATDC 是膀胱癌形成、进展和细胞毒性反应的关键决定因素。为了更好地了解 ATDC 在膀胱癌中的作用，我们提出以下研究： 目的 1：使用新型转基因小鼠模型来表征 ATDC 在膀胱癌发生、进展和转移中的作用，并确定炎症在诱导膀胱癌中 ATDC 表达中的作用。正常尿路上皮。目标 2：使用人和小鼠模型系统来表征 PTEN、RB1 和 p53 在 ATDC 介导的膀胱肿瘤形成和进展中的作用。目标 3：确定膀胱癌中的 ATDC 表达是否会导致进展为侵袭性疾病。目标 4：确定 ATDC 表达是否促进膀胱肿瘤对化疗的抵抗。这些研究将描述膀胱肿瘤发展的新机制和有价值的膀胱癌转基因模型。我们还将利用现有的人类细胞系和原发性人类肿瘤样本来阐明 ATDC 诱导膀胱癌并介导化疗耐药的分子机制。这些研究意义重大，因为了解 ATDC 在膀胱癌中的致癌活性可能会导致新的预后生物标志物和改进的人类治疗方法。