Oncogenic Function of ATDC in Bladder Cancer

ATDC 在膀胱癌中的致癌功能

• 批准号: 9017959
• 负责人: DIANE M SIMEONE
• 金额: $ 44.43万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 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 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9017959
• 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; Genes; Health; Hereditary Disease; Human; Human Cell Line; Inflammation; Lead; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Mediating; Methylation; Molecular; Neoplasm Metastasis; Oncogenes; Oncogenic; Organ; PTEN gene; Penetrance; Prognostic Marker; RB1 gene; Radiation; Resistance; Role; Sampling; Signal Transduction; TP53 gene; Therapeutic; Tissues; Transgenic Mice; Transgenic Model; Tumor Suppressor Genes; Up-Regulation; Urothelium; base; beta catenin; cancer initiation; cancer risk; chemotherapy; cytotoxic; improved; mouse model; new therapeutic target; novel; overexpression; promoter; 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(申请人提供)：膀胱癌是一种常见的致命疾病，但导致其发展的分子事件尚不完全清楚。我们最近发现了一个新的癌基因，共济失调-毛细血管扩张症D组互补(ATDC)，它在转基因小鼠中驱动膀胱肿瘤的发生和发展。这些肿瘤与人类的同类肿瘤难以区分。ATDC在人类浸润性膀胱癌中的表达升高(约70%)，并与化疗后较差的生存期有关。在其他类型的肿瘤中，ATDC结合P53，调节DNA损伤反应，并上调β-连环蛋白信号。在初步数据中，我们发现ATDC的表达是由炎症诱导的，与PTEN和RB1这两个与膀胱肿瘤发生有关的重要抑癌基因的表达降低有关，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、发展和细胞毒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，我们提出了以下研究：目的1：利用新型转基因小鼠模型，研究ATDC在膀胱癌发生、发展和转移中的作用，并确定炎症在诱导正常尿路上皮细胞ATDC表达中的作用。目的：利用人和小鼠膀胱肿瘤模型系统研究PTEN、RB1和P53在ATDC介导的膀胱肿瘤形成和发展中的作用。目的3：确定ATDC在膀胱癌中的表达是否推动了浸润性疾病的进展。目的4：探讨ATDC的表达是否促进了膀胱癌的化疗耐药。这些研究将表征一种新的膀胱癌发生机制和一种有价值的膀胱癌转基因模型。我们还将使用现有的人类细胞系和原代人类肿瘤样本来阐明ATDC诱导膀胱癌和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人类治疗方法的改进。