Objective In previous studies using oesophageal squamous cells from patients with Barrett's oesophagus (normal oesophageal squamous (NES)-B cells) and from patients without Barrett's oesophagus (NES-G cells), we showed that acid and bile salts induced caudal-related homeobox transcription factor 2 (CDX2) expression only in NES-B cells. CDX2, a transcription factor required to form intestinal epithelium, is a target of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signalling, which can be inhibited by aspirin. We explored mechanisms underlying differences between NES-B and NES-G cells in CDX2 expression and effects of aspirin on that CDX2 expression. Design We exposed NES-B and NES-G cells to acid and bile salts, with and without aspirin, and evaluated effects on IκB-NF-κB-PKAc complex activation, p65 NF-κB subunit function, and CDX2 expression. Results In both NES-B and NES-G cells, acid and bile salts activated nicotinamide adenine dinucleotide phosphate oxidase to generate H2O2, which activated the IκB-NF-κB-PKAc complex. NES-B cells exhibited higher levels of phosphorylated IκB and p65 and greater NF-κB transcriptional activity than NES-G cells, indicating greater IκB-NF-κB-PKAc complex activation by acid and bile salts in NES-B cells, and p65 siRNA prevented their increased expression of CDX2. Aspirin blocked IκB phosphorylation, p65 nuclear translocation, CDX2 promoter activation and CDX2 expression induced by acid and bile salts in NES-B cells. Conclusions Differences between NES-B and NES-G cells in NF-κB activation by acid and bile salts can account for their differences in CDX2 expression, and their CDX2 expression can be blocked by aspirin. These findings might explain why some patients with GORD develop Barrett's oesophagus while others do not, and why aspirin might protect against development of Barrett's oesophagus.

中文翻译：

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阿司匹林抑制巴雷特食管患者食管鳞状细胞中酸和胆汁盐刺激的 NF-κB 活化和 CDX2 表达

目的 在先前使用来自 Barrett 食管患者（正常食管鳞状细胞 (NES)-B 细胞）和非 Barrett 食管患者（NES-G 细胞）的食管鳞状细胞的研究中，我们发现酸和胆汁盐诱导尾端相关同源盒转录因子 2 (CDX2) 仅在 NES-B 细胞中表达。CDX2 是形成肠上皮所需的转录因子，是活化 B 细胞 (NF-κB) 信号传导的核因子 kappa-轻链增强子的靶标，可被阿司匹林抑制。我们探讨了 NES-B 和 NES-G 细胞在 CDX2 表达方面的潜在差异以及阿司匹林对该 CDX2 表达的影响的机制。设计 我们将 NES-B 和 NES-G 细胞暴露于酸和胆汁盐中，有或没有阿司匹林，并评估对 IκB-NF-κB-PKAc 复合物激活的影响，p65 NF-κB 亚基功能和 CDX2 表达。结果 在 NES-B 和 NES-G 细胞中，酸和胆汁盐激活烟酰胺腺嘌呤二核苷酸磷酸氧化酶生成 H2O2，从而激活 IκB-NF-κB-PKAc 复合物。与 NES-G 细胞相比，NES-B 细胞表现出更高水平的磷酸化 IκB 和 p65 以及更高的 NF-κB 转录活性，表明 NES-B 细胞中酸和胆汁盐以及 p65 siRNA 对 IκB-NF-κB-PKAc 复合物的激活更大阻止它们增加的 CDX2 表达。阿司匹林阻断了 NES-B 细胞中由酸和胆汁盐诱导的 IκB 磷酸化、p65 核易位、CDX2 启动子激活和 CDX2 表达。结论 NES-B 和 NES-G 细胞在酸和胆盐对 NF-κB 活化方面的差异可以解释它们在 CDX2 表达上的差异，并且它们的 CDX2 表达可以被阿司匹林阻断。这些发现可能解释了为什么一些 GORD 患者会发展为巴雷特食管，而另一些则不会，以及为什么阿司匹林可以防止巴雷特食管的发展。