Disruption of Transcription Networks in Esophageal Adenocarcinoma Tumorigenesis

摘要/摘要：食管腺癌(EAC)的发病率已上升超过 在过去的三十年里翻了六番。EAC患者的5年存活率不到15%，强调了 需要了解潜在的生物学，以确定新的治疗方法。慢性胃食道 反流病(GERD)，即酸性胆盐(ABS)异常反流到食道，影响更大 超过美国人口的20%。在这个计划项目中，我们假设APE1氧化还原之间相互作用 功能和异uglandins(IsoLGs)蛋白加合物促进关键致癌基因的激活和稳定性 转录网络在食道肿瘤发生中调节细胞存活和扩张。本节目 该项目利用主要研究人员的独特专业知识，并利用先进的遗传和 外科动物模型，三维体外模型，人体组织，患者来源的异种移植(PDX)，以及 创新技术。项目1研究APE1-氧化还原功能促进 回流条件下EACS中SOX9转录因子的激活机械学和功能研究将 探讨APE1氧化还原功能和IsoLGs加合物在调节SOX9促进癌细胞存活中的作用 和扩张。翻译研究将确定APE1氧化还原抑制剂在小鼠体内的有效性 模特们。项目2通过IsoLG蛋白加合物作为细胞反应来研究STAT3的新机制 由回流条件引起的氧化应激。翻译实验包括使用isolg。 抑制癌基因蛋白加合物形成和进展为EAC的抑制剂 巴雷特的肿瘤发生学。项目3调查了Sox4在EAC开发中的作用。中国的翻译研究 项目3包括测试FDA批准的抑制Sox4的药物，作为开发一种新的 治疗EACS的策略。本计划项目中的集成数据交换将使我们能够共同 探讨APE1氧化还原功能和IsoLG蛋白加合物在食道肿瘤发生中的作用。这个 三个拟议的核心为所有项目提供关键服务。管理核心(核心A)将管理 所有科学和财政问题，并促进研究互动。分子病理学核心(核心B) 将为动物和人类组织提供组织病理学和免疫组织化学服务。这个 生物统计和生物信息学核心(核心C)将在提供计算、 统计和生物信息学服务。通过这些项目和核心互动，我们将确定与生物相关的 可通过治疗靶向使EAC患者受益的致癌分子脆弱性

SUMMARY/ABSTRACT: The incidence of esophageal adenocarcinoma (EAC) has increased more than six-fold over the past three decades. EAC patients' 5-year survival rate is less than 15%, underscoring the need to understand the underlying biology to identify new therapeutic approaches. Chronic gastroesophageal reflux disease (GERD), where acidic bile salts (ABS) abnormally refluxate into the esophagus, affects more than 20% of the US population. In this program project, we hypothesize that interactions between APE1 redox functions and isolevuglandins (IsoLGs) protein adducts promote activation and stability of critical oncogenic transcription networks to mediate cell survival and expansion in esophageal tumorigenesis. This program project leverages unique expertise of the principal investigators and takes advantage of advanced genetic and surgical animal models, 3-dimensional in vitro models, human tissues, patient-derived xenografts (PDXs), and innovative technologies. Project 1 investigates mechanisms by which APE1-redox function promotes activation of SOX9 transcription factor in EACs under reflux conditions. Mechanistic and functional studies will explore the role of APE1 redox function and IsoLGs adducts in regulating SOX9 to promote cancer cell survival and expansion. Translational studies will determine the efficacy APE1 redox inhibitors using in vivo mouse models. Project 2 investigates novel mechanisms of STAT3 by IsoLG protein adducts, as a cellular response to oxidative stress induced by reflux conditions. The translational experiments include the use of isoLG inhibitors to suppress formation of oncogenic protein adducts and progression to EAC in animal models of Barrett’s tumorigenesis. Project 3 investigates the role SOX4 in EAC development. The translation studies in Project 3 include testing FDA-approved drugs that inhibit SOX4, as a proof of concept to develop a novel strategy to treat EACs. The integrated data exchange in this program project will enable us to collectively investigate the role of APE1 redox functions and IsoLG protein adducts in esophageal tumorigenesis. The three proposed cores deliver key services for all the projects. The Administrative Core (Core A) will manage all scientific and fiscal issues and facilitate research interactions. The Molecular Pathology Core (CORE B) will provide histopathology and immunohistochemistry services for animal and human tissues. The Biostatistics and Bioinformatics Core (CORE C) will play a central role in providing computational, statistical, and bioinformatics services. Via these Project and Core interactions we will identify biology-relevant oncogenic molecular vulnerabilities that can be therapeutically targeted to benefit EAC patients