Regulation of ATDC by TP63 and its role in bladder cancer

摘要 膀胱癌是一种常见的致命疾病，今年美国将有超过15，000人死于这种疾病。 年浸润性膀胱癌占新诊断膀胱癌的25%，通常会复发 作为致命的转移性疾病，几乎没有有效的治疗方法。浸润性膀胱癌可以是 在分子上分为管腔型或更具侵袭性的基底型， TP63与其他基底/鳞状肿瘤具有相同的分子特征。 我们已经鉴定了一种癌基因，共济失调-毛细血管扩张症D组互补基因（ATDC，也称为 TRIM29），其通常在人类膀胱癌中表达，并驱动启动和侵袭 转基因小鼠膀胱肿瘤的进展。已知ATDC结合p53，调节DNA损伤， 反应，上调β-连环蛋白信号传导，促进PTEN沉默，并作为触发肿瘤的开关 入侵虽然ATDC是人类膀胱癌的重要致癌驱动因素，但它通常不会突变 或扩增，调节其表达的机制未知。我们发现ATDC表达 标记显示基础表型的人浸润性膀胱癌，并且基础标记，TP 63， 其也已知促进侵袭，似乎调节ATDC的表达。因此我们假设 TP63在膀胱癌（以及可能的其他肿瘤）中诱导基础基因表达程序， 需要ATDC的上调，其促进肿瘤发生和侵袭性进展。更好地 为了表征TP63和ATDC在浸润性基底膀胱癌中的作用，我们提出了以下研究： 具体目的1：在体外表征TP63调节ATDC的机制。具体目标2： 研究TP63和ATDC在侵袭性进展中的作用。具体目标3： ATDC对体内基底膀胱癌发展的贡献。 与其他恶性肿瘤相比，膀胱癌的研究较少，导致对膀胱癌的认识有限。 驱动生物学和没有针对性的治疗方法。作为一名拥有临床和研究经验的医学肿瘤学家， 关注膀胱癌患者，我相信这里提出的研究是重要的，因为 了解ATDC和TP63在膀胱癌中的致癌活性可能会改善治疗效果， 为我的病人提供新的治疗方法和新的预后生物标志物。这项工作是创新的，因为我们将利用 新型转基因模型系统、人类样本、3D培养系统和下一代测序 技术（Bru-seq，ChIP-seq）来揭示膀胱中由ATDC和TP63驱动的肿瘤促进事件 癌这个建议也将支持我的职业发展，作为一个基础/转化研究，具体 关注膀胱癌，这是一个尚未满足临床需求的领域。

Abstract Bladder cancer is a common and deadly disease and over 15,000 people will die of this disease in the US this year. Invasive bladder cancers, which account for 25% of newly-diagnosed bladder cancers, commonly recur as lethal metastatic disease for which few effective treatments exist. Invasive bladder cancers can be molecularly classified as either luminal or the more aggressive basal subtypes which have high expression of TP63 and share molecular features with other basal/squamous tumors. We have identified an oncogene, Ataxia-Telangiectasia Group D Complementing gene (ATDC, also known as TRIM29), which is commonly expressed in human bladder cancers and drives initiation and invasive progression of bladder tumors in transgenic mice. ATDC is known to bind p53, modulate DNA damage responses, up-regulates -catenin signaling, promotes silencing of PTEN and acts as a switch triggering tumor invasion. While ATDC is an important oncogenic driver in human bladder cancers, it is not commonly mutated or amplified and the mechanism(s) regulating its expression are unknown. We find that ATDC expression marks human invasive bladder cancers which display a basal phenotype and that the basal marker, TP63, which is also known to promote invasion, appears to regulate expression of ATDC. We therefore hypothesize that TP63 induces a basal gene expression program in bladder cancer (and likely other tumors as well), requiring upregulation of ATDC which promotes tumorigenesis and invasive progression. To better characterize the role of TP63 and ATDC in invasive basal bladder cancer, we propose the following studies: SPECIFIC AIM 1: To characterize the mechanism(s) of TP63 regulation of ATDC in vitro. SPECIFIC AIM 2: To examine the role of TP63 and ATDC in invasive progression. SPECIFIC AIM 3: To characterize the contribution of ATDC to development of basal bladder cancers in vivo. Compared to other malignancies, bladder cancer is less studied resulting in a limited understanding of the driving biology and no targeted therapeutic approaches. As a medical oncologist with a clinical and research focus on patients with bladder cancer, I believe the studies proposed here are significant because understanding ATDC and TP63’s oncogenic activity in bladder cancer may lead to improved therapeutic approaches and new prognostic biomarkers for my patients. This work is innovative because we will utilize novel transgenic model systems, human samples, 3D culture systems, and next generation sequencing technology (Bru-seq, ChIP-seq) to uncover the tumor promoting events driven by ATDC and TP63 in bladder cancer. This proposal will also support my career development as a basic/translational research with specific focus on bladder cancer, an area of unmet clinical need.