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.

项目概要 膀胱癌最常见于早期诊断，此时癌症尚未侵入膀胱壁 或者已经最低限度地这样做了。治疗方法是切除肿瘤，将其打碎并通过 尿道。早期膀胱癌患者很少死于这种疾病，尽管肿瘤通常 复发，需要额外切除。一部分患者进展为晚期疾病，其中 往往是致命的。早期膀胱癌的治疗旨在减少复发和进展 疾病晚期。然而，很难预测哪些患者会复发和进展。可用的 治疗方法也主要限于经尿道切除和注射减毒杆菌（一种细菌） 进入膀胱，引起炎症。后一种治疗可降低复发风险，并可能 进展，但很痛苦，并可能导致严重的排尿困难和偶尔的败血症。更好的 需要预测和治疗这种疾病的方法。 在正在进行的实验中，我们发现早期膀胱癌的进展更为常见， 表达高水平的 Spalt-like-4 (SALL4)。该基因通常不在成人组织中表达，而是在 在发育中的胚胎中表达。它是一种转录因子，可结合 DNA 并改变其他基因的表达 基因。先前的研究表明SALL4在许多癌症类型中表达，并且表达驱动肿瘤 生长和增殖以及其他肿瘤类型的侵袭行为。我们的实验也同样 研究表明，SALL4 可能会促进膀胱癌的细胞增殖，这一特征与膀胱癌风险增加相关 其他研究中的复发和进展。我们还有证据表明 SALL4 直接激活细胞周期 细胞增殖的基础过程。了解 SALL4 将使膀胱癌患者受益 在这种疾病中，因为它可以用来预测哪些患者会复发和进展，并且可能成为治疗的目标 治疗。 鉴于这些发现，我们假设 SALL4 驱动早期膀胱癌的细胞增殖， 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 具有这些具体目标的假设：（1）建立参与基因表达的关系 细胞周期，以及 SALL4 结合在调节其表达的 DNA 区域； (2) 确定直接 减少或增加 SALL4 表达对细胞系和小鼠异种移植模型的影响，特别是 对细胞周期活性、细胞增殖、肿瘤生长和侵袭的影响。