慢性胃食道反流病是酸性胆汁盐（ABS）反流至食道的主要风险因素，同时也是食道腺癌（EAC）的主要风险因素。我们研究了ABS在促进EAC上皮间质转化（EMT）中的作用。分析RNA测序数据和公共数据库以揭示EMT通路富集和患者无复发生存率。利用细胞模型、pL2-IL1β转基因小鼠、去鉴定的EAC患者来源的异种移植物（PDXs）和组织来研究EAC中的EMT。对公共数据库和RNA测序数据的分析表明，在EAC中EMT信号通路富集和激活显著。ABS诱导了EMT过程的多个特征，如E-钙粘降解、波形蛋白上调和ß-catenin信号通路激活以及EMT转录因子的激活。这些变化与形态学改变和细胞迁移和侵袭能力的增强相关。机制上，ABS通过MMP14依赖的蛋白酶级联反应诱导了E-钙粘的降解。AP受损/无嘌呤内切酶（APE1），也被称为还原氧化态1，是一种重要的多功能蛋白质。APE1沉默或其氧化还原特异性抑制剂（E3330）使MMP14下调并消除了ABS诱导的EMT。在人类EAC组织和L2-IL1ß转基因小鼠的鳞状柱状联合处，APE1和MMP14的共表达水平与E-钙粘的表达呈负相关。具有APE1高和EMT高标志的EAC患者的复发无生存率低于水平低的患者。此外，使用E3330处理PDXs抑制了EMT特征并抑制了肿瘤侵袭。反流条件通过APE1氧化还原依赖的E-钙粘降解促进了EMT。APE1氧化还原功能抑制剂在EAC中具有治疗作用。©作者（或其雇主）2023。不可进行商业再利用。请参阅权利和权限。由BMJ出版。

Chronic gastro-oesophageal reflux disease, where acidic bile salts (ABS) reflux into the oesophagus, is the leading risk factor for oesophageal adenocarcinoma (EAC). We investigated the role of ABS in promoting epithelial-mesenchymal transition (EMT) in EAC.RNA sequencing data and public databases were analysed for the EMT pathway enrichment and patients' relapse-free survival. Cell models, pL2-IL1β transgenic mice, deidentified EAC patients' derived xenografts (PDXs) and tissues were used to investigate EMT in EAC.Analysis of public databases and RNA-sequencing data demonstrated significant enrichment and activation of EMT signalling in EAC. ABS induced multiple characteristics of the EMT process, such as downregulation of E-cadherin, upregulation of vimentin and activation of ß-catenin signalling and EMT-transcription factors. These were associated with morphological changes and enhancement of cell migration and invasion capabilities. Mechanistically, ABS induced E-cadherin cleavage via an MMP14-dependent proteolytic cascade. Apurinic/apyrimidinic endonuclease (APE1), also known as redox factor 1, is an essential multifunctional protein. APE1 silencing, or its redox-specific inhibitor (E3330), downregulated MMP14 and abrogated the ABS-induced EMT. APE1 and MMP14 coexpression levels were inversely correlated with E-cadherin expression in human EAC tissues and the squamocolumnar junctions of the L2-IL1ß transgenic mouse model of EAC. EAC patients with APE1high and EMThigh signatures had worse relapse-free survival than those with low levels. In addition, treatment of PDXs with E3330 restrained EMT characteristics and suppressed tumour invasion.Reflux conditions promote EMT via APE1 redox-dependent E-cadherin cleavage. APE1-redox function inhibitors can have a therapeutic role in EAC.© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.