The Role of APE1/Ref-1 in Reflux-Induced Epithelial-Mesenchymal Transition in Benign Barrett's Metaplasia: A Novel Target for Preventing Recurrent Barrett's Esophagus After Radiofrequency Ablation

APE1/Ref-1 在良性 Barrett 化生中反流诱导的上皮间质转化中的作用：射频消融后预防 Barrett 食管复发的新靶点

• 批准号: 10532359
• 负责人: RHONDA F SOUZA
• 金额: $ 36.1万
• 依托单位: BAYLOR RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-13 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10532359
• 关键词: Ablation; Abnormal Cell; Acids; Acute; Back; Barrett Epithelium; Barrett Esophagus; Benign; Bile fluid; Burn injury; Cell Survival; Cells; Complex; Complication; Data; Development; Dysplasia; Endowment; Epithelial Cells; Epithelium; Esophageal Adenocarcinoma; Esophagus; Event; Exposure to; Family member; Frequencies; Gastric Juice; Gastroesophageal reflux disease; Gland; Goals; In Vitro; Injury; Intestinal Metaplasia; Intestines; Lamina Propria; Malignant Neoplasms; Malignant neoplasm of esophagus; Mediating; Mesenchymal; Metaplasia; Molecular; Oxidation-Reduction; Oxidative Stress; Oxidative Stress Induction; Pathway interactions; Patients; Performance; Pharmaceutical Preparations; Play; Preventive; Probability; Procedures; Process; Production; Public Health; Publishing; Radiofrequency Interstitial Ablation; Reactive Oxygen Species; Recurrence; Reflux; Reporting; Resistance; Risk; Risk Factors; Role; Signal Induction; Signal Transduction; Source; Squamous Epithelium; Vascular Endothelial Growth Factors; bile salts; cancer prevention; cancer risk; cell motility; cost effective; epithelial to mesenchymal transition; experimental study; gene repression; genetic corepressor; in vivo; inhibitor; migration; neoplastic; novel; premalignant; prevent; programs; promoter; randomized trial; targeted treatment; transcription factor; treatment choice; tumor; wound healing

Project Summary Barrett’s esophagus, the condition in which the normal squamous lining of the esophagus is replaced by a metaplastic intestinal-type lining, is a risk factor for esophageal adenocarcinoma. This deadly cancer can be prevented by radiofrequency ablation (RFA), an endoscopic procedure that burns away the cancer-prone metaplastic lining. Presently, RFA is used only to eradicate Barrett’s esophagus that has precancerous changes called dysplasia. After RFA, patients require regular endoscopic cancer surveillance because Barrett’s metaplasia recurs frequently. Although RFA potentially could prevent cancer for the millions of patients with non-dysplastic Barrett’s esophagus, RFA cannot be cost-effective for them unless it permanently eradicates Barrett’s metaplasia. A condition called subsquamous intestinal metaplasia (SSIM) might underlie the frequent recurrences of Barrett’s esophagus after RFA. In SSIM, Barrett’s cells are located under a layer of normal esophageal squamous lining that shields them from destruction by RFA. Most Barrett’s patients have SSIM, which could be the nidus for recurrent metaplasia after RFA. Our published data suggest that SSIM develops when Barrett’s cells undergo a process called epithelial-mesenchymal transition (EMT), which is a wound-healing event triggered by gastroesophageal reflux disease (GERD). EMT endows Barrett’s cells with migratory abilities that enable them to move under the adjacent squamous lining. EMT also activates cell survival pathways that could enable Barrett’s cells wounded by RFA to survive. Thus, EMT appears to underlie the development of SSIM, and EMT might well underlie the high frequency of metaplasia recurrences after RFA. In Barrett’s cells, we have reported that acid and bile (the damaging factors in gastric juice that refluxes into the esophagus in GERD patients) induce oxidative stress that results in the accumulation of a molecule called HIF-1α. We also published that acidic bile salts induce signaling through a molecular pathway that causes Barrett’s cells to increase their production of ZEB1, a molecule that plays a key role in inducing the EMT that triggers the cell motility leading to the development of SSIM. Our new experiments demonstrate that acidic bile salts activate the function of a molecule called APE1/Ref-1 that is required for activation of HIF-1α. We show that activated HIF-1α mediates increased production of the ZEB1 that induces EMT. Thus, we hypothesize that GERD-induced APE1/Ref-1 function that activates HIF-1α is the pivotal event in initiating EMT that enables Barrett’s cells to form SSIM and to survive RFA, and that these events might be prevented by drugs that inhibit APE1/Ref-1. The aims of this study are to elucidate the mechanism(s) whereby APE1/Ref- 1 signaling and HIF-1α activation contribute to the induction of EMT, and to explore the role of the APE1/Ref-1- HIF-1α signaling axis in EMT induced by exposure to acidic bile salts in Barrett’s esophagus. Our ultimate goal is to determine how SSIM develops and how a targeted treatment might be used to prevent that development, findings that could provide the means to eradicate Barrett’s esophagus and its cancer risk permanently.

项目摘要 Barrett‘s食道，在这种情况下，正常的食道鳞状衬里被 化生肠型衬里，是食管腺癌的危险因素。这种致命的癌症可能是 通过射频消融(RFA)预防，这是一种内窥镜手术，可以烧毁易患癌症的人 化生衬里。目前，射频消融仅用于根治有癌前病变的巴雷特食道。 这些变化称为发育不良。RFA后，患者需要定期进行内窥镜癌症监测，因为 巴雷特化生经常复发。尽管RFA有可能预防数百万人的癌症 对于非发育不良Barrett‘s食道的患者，RFA不可能对他们具有成本效益，除非永久 根治巴雷特的化生。一种称为鳞状下肠化生(SSIM)的疾病可能是其基础。 射频消融术后Barrett‘s食道频繁复发。在SSIM中，Barrett的细胞位于 正常的食道鳞状衬里，保护它们免受RFA的破坏。大多数巴雷特的病人都有 SSIM可能是RFA术后复发性化生的病灶。我们公布的数据表明，SSIM 当Barrett细胞经历称为上皮-间充质转化(EMT)的过程时发生，这是一种 由胃食道反流病(GERD)引发的伤口愈合事件。EMT赋予巴雷特细胞 迁徙能力，使它们能够在相邻的鳞状衬里下移动。EMT还能激活细胞 能够使射频损伤的巴雷特细胞存活的生存途径。因此，EMT似乎是基础 SSIM和EMT的发展很可能是术后高频率的化生复发的基础。 RFA。在巴雷特细胞中，我们已经报道了酸和胆汁(胃液中回流的破坏因素) 进入GERD患者的食道)诱导氧化应激，导致分子积累 名为HIF-1α。我们还发表了酸性胆盐通过一种分子途径诱导信号传递的文章 使巴雷特细胞增加ZEB1的产生，ZEB1分子在诱导 触发细胞运动导致SSIM发生的EMT。我们的新实验证明 酸性胆盐可激活激活缺氧诱导因子-1α所需的APE1/Ref-1分子的功能。 我们发现，激活的HIF-1α介导了ZEB1的产生增加，从而诱导了EMT。因此，我们 假设GERD诱导的APE1/Ref-1功能激活HIF-1α是启动的关键事件 使Barrett细胞形成SSIM并存活于RFA的EMT，这些事件可能被预防 通过抑制APE1/Ref-1的药物。本研究的目的是阐明APE1/Ref-1/Ref-1的作用机制(S)。 1信号转导和缺氧诱导因子-1α的激活参与了子宫内膜间质转化的诱导，并探讨了APE1/Ref-1-1的作用。 低氧诱导因子-1α信号轴在酸性胆盐暴露于巴雷特食道诱导的子宫内膜癌中的作用。我们的终极目标 是确定SSIM是如何发展的，以及如何使用靶向治疗来防止这种发展， 这些发现可能会提供永久根除巴雷特食道及其癌症风险的方法。