The Role of Transcription Factors in Driving Aggressive Phenotype in Non-Invasive Bladder Cancer

转录因子在驱动非侵袭性膀胱癌侵袭性表型中的作用

• 批准号: 10182200
• 负责人: Joshua I Warrick
• 金额: $ 41.7万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10182200
• 关键词: Address; Adult; Aggressive behavior; Archives; Attenuated; Automobile Driving; Bacillus; Bacteria; Behavior; Binding; Binding Sites; Biological Assay; Bladder; Cancer Biology; Cancer cell line; Cell Cycle; Cell Line; Cell Proliferation; ChIP-seq; Clinical; Computational Biology; Coupled; DNA; DNA Binding; Data; Development; Diagnosis; Disease; Disease model; Early treatment; Embryo; Excision; Flow Cytometry; Freezing; Gene Expression; Genes; Human; Immunohistochemistry; In Vitro; Inflammation; Institutes; Institution; Interdisciplinary Study; Malignant neoplasm of urinary bladder; Methods; Molecular Profiling; Morbidity - disease rate; Mus; Oncogenes; Pain; Pathology; Patients; Peptides; Pharmaceutical Preparations; Pharmacology; Phenotype; Process; Public Health; Recurrence; Regulatory Element; Regulon; Research Support; Risk; Role; S-Phase Fraction; Sampling; Sepsis; Specimen; Therapeutic Intervention; Tissues; Transurethral Resection; Tumor Cell Invasion; Urethra; Urination; Urology; Work; Xenograft Model; animal facility; antitumor effect; cancer recurrence; cancer type; cdc Genes; cis acting element; effective therapy; embryonic stem cell; experimental study; genome sciences; improved; in vivo; innovation; loss of function; neoplastic cell; non-muscle invasive bladder cancer; patient subsets; personalized medicine; pluripotency factor; preclinical study; predictive signature; prevent; prognostic assays; programs; targeted treatment; therapeutic target; transcription factor; transcriptome sequencing; tumor; tumor growth

Project summary Bladder cancer is most commonly diagnosed at an early stage, where it has not invaded into the bladder wall or has done so minimally. Treatment is resection of the tumor, by fragmenting it and removing through the urethra. Patients with early stage bladder cancer uncommonly die from the disease, though the tumor usually recurs, requiring additional resections. A subset of patients progresses to advanced stage disease, with is often lethal. Treatment of early stage bladder cancer is aimed at reducing recurrence and progression to advanced stage disease. However, it is difficult to predict which patients will recur and progress. Available treatments are also largely limited to transurethral resection and instillation of attenuated bacillus (a bacterium) into the bladder, which induces inflammation. This latter treatment reduces risk of recurrence and likely progression, but is painful and can cause profound difficulties with urination and occasional sepsis. Better methods are needed to prognosticate and treat this disease. In ongoing experiments, we have found that progression is more common in early stage bladder cancers that express high levels of Spalt-like-4 (SALL4). This gene is typically not expressed in adult tissues, but is rather expressed in developing embryos. It is a transcription factor, which binds DNA and alters expression of other genes. Prior studies have shown SALL4 is expressed in many cancer types, and expression drives tumor growth and proliferation, as well as aggressive behavior in other tumor types. Our experiments have likewise shown SALL4 may drive cellular proliferation in bladder cancer, a feature associated with increased risk of recurrence and progression in other studies. We also have evidence SALL4 directly activates the cell cycle, the process underlying cellular proliferation. Patients with bladder cancer would benefit from understanding SALL4 in this disease, as it could be used to predict which patients will recur and progression, and could be a target of therapy. Given these findings, We hypothesize that SALL4 drives cellular proliferation in early stage bladder cancer, thereby driving stage progression, specifically by directly activating cell cycle programs. We will address this hypothesis with these Specific Aims: (1) establish the relationship between expression of genes involved in the cell cycle, and SALL4 binding at DNA regions that regulate their expression; and (2) determine the direct effects of reducing or increasing SALL4 expression in cell lines and mouse xenograft models, specifically the effects on activity of the cell cycle, cellular proliferation, tumor growth, and invasion.

项目摘要 膀胱癌最常见于早期尚未入侵膀胱壁 或做到这一点很少。治疗是切除肿瘤，通过破碎并通过肿瘤切除 尿道。早期膀胱癌的患者罕见地死于该疾病，尽管肿瘤通常 复发，需要其他切除。一部分患者发展为晚期疾病，iS 经常致命。早期膀胱癌的治疗旨在将复发和进展减少到 晚期舞台疾病。但是，很难预测哪些患者会复发和进展。可用的 治疗也很大程度上仅限于尿道切除和减毒芽孢杆菌的滴注（细菌） 进入膀胱，引起炎症。后一种治疗降低了复发的风险，可能 进展，但很痛苦，可能会因排尿和偶尔败血症带来深远的困难。更好的 需要预测和治疗该疾病的方法。 在正在进行的实验中，我们发现进展在早期膀胱癌中更为常见 表达高水平的类似Spalt Like-4（SALL4）。该基因通常在成人组织中不表达，而是 在开发胚胎中表达。它是一个转录因子，它结合了DNA并改变了其他的表达 基因。先前的研究表明SALL4在许多癌症类型中表达，表达驱动肿瘤 其他肿瘤类型的生长和增殖以及侵略性行为。我们的实验也有 显示的SALL4可能会驱动膀胱癌中的细胞增殖，该功能与增加的风险有关 在其他研究中的复发和进展。我们还有证据SALL4直接激活细胞周期，即 过程基础的细胞增殖。膀胱癌患者了解SALL4将受益于 在这种疾病中，可以用来预测哪些患者会复发和进展，并且可能是 治疗。 鉴于这些发现，我们假设SALL4在早期膀胱癌中驱动细胞增殖， 从而驱动阶段进展，特别是通过直接激活细胞周期程序。我们将解决这个问题 以这些特定目的的假设：（1）建立与参与基因的表达之间的关系 细胞周期和在调节其表达的DNA区域的SALL4结合； （2）确定直接 在细胞系和小鼠异种移植模型中还原或增加SALL4表达的影响，特别是 对细胞周期活性，细胞增殖，肿瘤生长和侵袭的影响。