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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要巴雷特食管，食管正常鳞状内膜被食管替代的病症肠型内膜化生，是食管腺癌这种致命癌症的危险因素。射频消融 (RFA) 是一种内窥镜手术，可以烧掉易患癌症的部位目前，射频消融仅用于根除癌前病变的巴雷特食管。 RFA 后发生称为发育不良的变化，患者需要定期进行内镜癌症监测，因为尽管 RFA 可能可以预防数百万人的癌症，但 Barrett 化生经常复发。对于患有非发育不良巴雷特食管的患者，射频消融对他们来说不具有成本效益，除非它是永久性的根除巴雷特化生可能是一种称为鳞状下肠化生（SSIM）的疾病。 RFA 后 Barrett 食管频繁复发在 SSIM 中，Barrett 细胞位于一层食管下。大多数巴雷特氏症患者都有正常的食管鳞状内膜，可以保护它们免受 RFA 的破坏。 SSIM，这可能是 RFA 后复发性化生的病灶。我们发表的数据表明 SSIM。当 Barrett 细胞经历一个称为上皮间质转化 (EMT) 的过程时，就会发生这种情况，这是一个胃食管反流病 (GERD) 引发的伤口愈合事件导致 Barrett 细胞死亡。使它们能够在邻近鳞状内膜下移动的迁移能力也会激活细胞。因此，EMT 似乎是 RFA 损伤的巴雷特细胞存活的基础。 SSIM 的发展和 EMT 很可能是化生术后高频率复发的基础。 RFA。我们报道了巴雷特细胞中的酸和胆汁（胃液中反流的破坏性因素）。进入胃食管反流病患者的食道）诱导氧化应激，导致分子积累我们还发表了酸性胆汁盐通过分子途径诱导信号传导的研究。导致 Barrett 细胞增加 ZEB1 的产生，ZEB1 是一种在诱导 EMT 触发细胞运动，导致 SSIM 的发展。我们的新实验证明了这一点。酸性胆汁盐可激活 APE1/Ref-1 分子的功能，该分子是激活 HIF-1α 所必需的。我们发现激活的 HIF-1α 会介导 ZEB1 的产生增加，从而诱导 EMT。 GERD 诱导的 APE1/Ref-1 功能激活 HIF-1α 是启动的关键事件 EMT 使 Barrett 细胞能够形成 SSIM 并在 RFA 中存活，并且这些事件可能会被预防本研究的目的是阐明 APE1/Ref-1 的抑制机制。 1 信号传导和 HIF-1α 激活有助于诱导 EMT，并探讨 APE1/Ref-1- 的作用巴雷特食管中暴露于酸性胆汁盐诱导的 EMT 中的 HIF-1α 信号轴我们的最终目标。是确定 SSIM 如何发展以及如何使用针对性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。