Aspirin prevents NF-kappa B activation and CDX2 expression stimulated by acid and bile salts in oesophageal squamous cells of patients with Barrett's oesophagus

作者：Huo Xiaofang; Zhang Xi; Yu Chunhua; Cheng Edaire; Zhang Qiuyang; Dunbar Kerry B; Pham Thai H; Lynch John P; Wang David H; Bresalier Robert S; Spechler Stuart J; Souza Rhonda F^*

来源：Gut, 2018, 67(4): 606-615.

DOI：10.1136/gutjnl-2016-313584

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-kappa B) 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 I.B-NF-kappa B-PKAc complex activation, p65 NF-kappa B 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 I kappa B-NF-kappa B-PKAc complex. NES-B cells exhibited higher levels of phosphorylated I kappa B and p65 and greater NF-kappa B transcriptional activity than NES-G cells, indicating greater I kappa B-NF-kappa B-PKAc complex activation by acid and bile salts in NES-B cells, and p65 siRNA prevented their increased expression of CDX2. Aspirin blocked I kappa B 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-kappa B 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.

• 出版日期2018-4