Elucidating Novel APE1 Redox-Dependent Functions in Esophageal Adenocarcinoma

阐明食管腺癌中新型 APE1 氧化还原依赖性功能

基本信息

批准号：
10662300
负责人：
WAEL EL-RIFAI
金额：
$ 40.57万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-08 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10662300
关键词：
3-Dimensional Affinity Barrett Esophagus Bioinformatics Biological Biology Biometry Cancer Model Cell Survival Cells Chronic Cisplatin Clinical Compensation Complex Cysteine DNA Binding DNA Binding Domain DNA-(apurinic or apyrimidinic site) lyase Development Diagnostic Environment Esophageal Adenocarcinoma Esophagus Event Experimental Designs Exposure to Gastroesophageal reflux disease Genetic Genetic Transcription Human Incidence Inflammation Malignant Neoplasms Medical Molecular Molecular Biology Oncogenic Oncology Organoids Outcome Oxidation-Reduction Oxidative Stress Pathology Patients Precancerous Conditions Property Proteins Reagent Reflux Regulation Reproducibility Resistance Risk Factors Role SOX4 gene Signal Transduction Stress Survival Rate Therapeutic Therapeutic Intervention Tissue Model Tissue Sample Tissues United States Western World Work adduct bile salts cancer cell carcinogenicity chemotherapeutic agent chemotherapy clinically significant driving force epigenetic regulation esophageal carcinogenesis evidence base experience fitness functional outcomes human tissue in vitro Model molecular pathology mouse model neoplastic cell novel novel therapeutic intervention overexpression patient derived xenograft model pharmacologic prognostic response therapy resistant tool transcription factor tumorigenesis tumorigenic

项目摘要

ABSTRACT/SUMMARY The incidence of esophageal adenocarcinoma (EAC) has increased more than six-fold over the past three decades. Chronic gastroesophageal reflux disease (GERD), where acidic bile salts abnormally refluxate into the esophagus, leads to the development of Barrett’s esophagus (BE), a premalignant condition that is the main risk factor for EAC. We and others have shown that chronic exposure to acidic bile salts induces inflammation and is associated with a dramatic increase in the burden of oxidative stress; believed to be the main driving forces for disruption of cellular signaling mechanisms and the development of EAC. It is unknown how tumorigenic esophageal cells escape the oxidative effects of acidic bile salts reflux and also become resistant to currently used chemotherapeutic agents. Alterations in the redox status of reactive cysteine residues, located within the DNA-binding domain of redox-sensitive transcription factors (TFs), can suppress TFs’ DNA binding affinity and transcription activity. Therefore, the cellular redox capacity is paramount in promoting activity of oncogenic transcription factors, protecting tumorigenic cells and promoting their survival and expansion. This project builds upon collective interaction among the three projects generating several novel preliminary findings. We have shown that AP endonuclease 1 (APE1) redox activity was required for activation of tumorigenic transcription factors such as SOX9 in response to exposure to reflux and chemotherapeutics. As part of scientific integration in this P01, working with Projects 2 and 3, we also found that high levels of reactive isolevuglandins (isoLGs) protein adducts promote stability of SOX9. As a result of these molecular events, EACs develop intrinsic and acquired resistance to standard chemotherapeutic. Based on our preliminary results, we aim to investigate the role of APE1-reodx function in promoting SOX9 activation in EACs. In Aim 1, we will investigate the role of APE1 and isoLG adducts in regulating SOX9 stability and activity. The functional outcome of APE1-SOX9 network is investigated in Aim 2. The clinical significance and therapeutic potential of targeting APE1 redox activity will be determined in Aim 3. Understanding biology- relevant molecular functions, the focus of this P01 and this project, is a key step for developing evidence- based therapeutic approaches that are founded on the biology and molecular underpinning of EAC. Upon completion of our work, we expect to uncover a new paradigm for understanding the biology of EAC to facilitate the development of novel medical treatments for this deadly cancer.

摘要/总结食管腺癌（EAC）的发病率比过去增加了六倍多三十年来，慢性胃食管反流病（GERD），其中酸性胆汁盐异常反流。进入食管，导致巴雷特食管 (BE) 的发展，这是一种癌前病变，我们和其他人已经证明，长期接触酸性胆盐会诱发 EAC。炎症并与氧化应激负担的急剧增加有关；细胞信号传导机制破坏和 EAC 发展的主要驱动力尚不清楚。致瘤性食管细胞如何逃避酸性胆汁盐反流的氧化作用并变得对目前使用的化疗药物具有耐药性。反应性半胱氨酸氧化还原状态的改变。残基位于氧化还原敏感转录因子 (TF) 的 DNA 结合域内，可以抑制 TF 的 DNA 结合亲和力和转录活性因此，细胞氧化还原能力至关重要。促进致癌转录因子的活性，保护致瘤细胞并促进其生存该项目建立在三个项目之间的集体互动的基础上，产生了几个项目。新的初步发现表明，AP 核酸内切酶 1 (APE1) 氧化还原活性是暴露于回流和作为本 P01 科学整合的一部分，我们还与项目 2 和 3 合作发现了这一点。高水平的反应性异黄酮 (isoLG) 蛋白加合物可促进 SOX9 的稳定性。这些分子事件使 EAC 对标准化疗产生内在的和获得性的耐药性。根据我们的初步结果，我们旨在研究 APE1-reodx 功能在促进 SOX9 激活中的作用在 EAC 中，我们将研究 APE1 和 isoLG 加合物在调节 SOX9 稳定性和目标 2 中研究了 APE1-SOX9 网络的功能结果。临床意义和作用。针对 APE1 氧化还原活性的治疗潜力将在目标 3 中确定。了解生物学- 相关的分子功能是本 P01 和本项目的重点，是开发证据的关键步骤- 基于 EAC 的生物学和分子基础的治疗方法。完成我们的工作后，我们期望发现一种新的范式来理解 EAC 的生物学促进针对这种致命癌症的新疗法的开发。