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: 10337291
• 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 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10337291
• 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; Epithelial; Epithelial Cells; Esophageal Adenocarcinoma; Esophagus; Event; Exposure to; Family member; Frequencies; Gastric Juice; Gastroesophageal reflux disease; Gland; Goals; In Vitro; Injury; Intestinal Metaplasia; Intestines; Lamina Propria; Lead; Malignant Neoplasms; Malignant neoplasm of esophagus; Mediating; Mesenchymal; Metaplasia; Molecular; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Patients; Performance; Pharmaceutical Preparations; Play; Preventive; Procedures; Process; Production; Public Health; Publishing; Radiofrequency Interstitial Ablation; Reactive Oxygen Species; Recurrence; Reflux; Reporting; Resistance; Risk; Risk Factors; Role; Signal Transduction; Source; Squamous Epithelium; Vascular Endothelial Growth Factors; bile salts; cancer prevention; cancer risk; cell motility; cost effective; experimental study; gene repression; genetic corepressor; in vivo; inhibitor; 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 巴雷特食管，其中食管的正常鳞状衬里被替代的状况， 化生性膀胱型内衬是食管腺癌的危险因素。这种致命的癌症可能是 通过射频消融术（RFA），一种内窥镜手术， 化生衬里目前，RFA仅用于根除具有癌前病变的巴雷特食管。 称为发育不良的变化。RFA后，患者需要定期进行内镜癌症监测，因为 巴雷特化生经常复发。尽管RFA可能会预防数百万人的癌症， 对于非异型增生Barrett食管患者，RFA对他们来说不具有成本效益，除非永久性地 能根除巴雷特化生一种叫做亚鳞状肠上皮化生（SSIM）的疾病可能是 射频消融后Barrett食管的频繁复发。在SSIM中，巴雷特细胞位于一层 正常的食管鳞状衬里，保护他们免受RFA的破坏。大多数巴雷特的病人 SSIM，可能是RFA后复发性化生的病灶。我们公布的数据表明，SSIM 当巴雷特细胞经历一个称为上皮-间充质转化（EMT）的过程时， 胃食管反流病（GERD）引发的伤口愈合事件。急救小组赋予巴雷特的细胞 迁移能力，使他们能够在相邻的鳞状衬里下移动。EMT还激活细胞 存活途径，可以使被RFA损伤的巴雷特细胞存活。因此，EMT似乎是 SSIM和EMT的发展很可能是术后化生复发率高的原因。 射频消融在Barrett细胞中，我们已经报道了酸和胆汁（胃液中回流的破坏因子）， 进入GERD患者的食管）诱导氧化应激，导致一种分子的积累 称为HIF-1α。我们还发表了酸性胆汁盐通过分子途径诱导信号传导， 导致巴雷特细胞增加ZEB 1的产生，ZEB 1是一种在诱导细胞凋亡中起关键作用的分子。 EMT触发细胞运动，导致SSIM的发展。我们的新实验表明， 酸性胆汁盐激活一种称为APE 1/Ref-1的分子的功能，这种分子是激活HIF-1α所必需的。 我们发现激活的HIF-1α介导了诱导EMT的ZEB 1的产生增加。因此我们 假设GERD诱导的激活HIF-1α的APE 1/Ref-1功能是启动 EMT使Barrett细胞能够形成SSIM并在RFA中存活，并且这些事件可能被预防 抑制APE 1/Ref-1的药物。本研究的目的是阐明APE 1/Ref- 1信号通路和HIF-1α激活参与EMT的诱导，并探讨APE 1/Ref-1-1在EMT诱导中的作用。 Barrett食管酸性胆盐诱导EMT的HIF-1α信号轴我们的最终目标 是确定SSIM是如何发展的，以及如何使用靶向治疗来预防这种发展， 这些发现可以提供永久根除巴雷特食管及其癌症风险的方法。