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

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Abstract

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-κ 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 Iκ B-NF-κ B-PKAc complex activation, p65 NF-κ 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 H 2 O 2, which activated the Iκ B-NF-κ B-PKAc complex. NES-B cells exhibited higher levels of phosphorylated Iκ B and p65 and greater NF-κ B transcriptional activity than NES-G cells, indicating greater Iκ B-NF-κ B-PKAc complex activation by acid and bile salts in NES-B cells, and p65 siRNA prevented their increased expression of CDX2. Aspirin blocked Iκ 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-κ 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.

Original languageEnglish (US)
Pages (from-to)606-615
Number of pages10
JournalGut
Volume67
Issue number4
DOIs
StatePublished - Apr 1 2018

Fingerprint

Barrett Esophagus
Bile Acids and Salts
Aspirin
Epithelial Cells
Gastrin-Secreting Cells
B-Lymphocytes
Homeobox Genes
Intestinal Mucosa
NADP
Small Interfering RNA
Oxidoreductases
Phosphorylation

Keywords

  • INFLAMMATION
  • OESOPHAGEAL DISEASE
  • OESOPHAGEAL REFLUX

ASJC Scopus subject areas

  • Gastroenterology

Cite this

@article{74572fd4d08a4f6094630dfc7af6d263,
title = "Aspirin prevents NF-κ B activation and CDX2 expression stimulated by acid and bile salts in oesophageal squamous cells of patients with Barrett's oesophagus",
abstract = "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-κ 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 Iκ B-NF-κ B-PKAc complex activation, p65 NF-κ 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 H 2 O 2, which activated the Iκ B-NF-κ B-PKAc complex. NES-B cells exhibited higher levels of phosphorylated Iκ B and p65 and greater NF-κ B transcriptional activity than NES-G cells, indicating greater Iκ B-NF-κ B-PKAc complex activation by acid and bile salts in NES-B cells, and p65 siRNA prevented their increased expression of CDX2. Aspirin blocked Iκ 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-κ 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.",
keywords = "INFLAMMATION, OESOPHAGEAL DISEASE, OESOPHAGEAL REFLUX",
author = "Xiaofang Huo and Xi Zhang and Chunhua Yu and Edaire Cheng and Qiuyang Zhang and Dunbar, {Kerry B.} and Pham, {Thai H.} and Lynch, {John P.} and Wang, {David H.} and Bresalier, {Robert S.} and Spechler, {Stuart J.} and Souza, {Rhonda F.}",
year = "2018",
month = "4",
day = "1",
doi = "10.1136/gutjnl-2016-313584",
language = "English (US)",
volume = "67",
pages = "606--615",
journal = "Gut",
issn = "0017-5749",
publisher = "BMJ Publishing Group",
number = "4",

}

TY - JOUR

T1 - Aspirin prevents NF-κ B activation and CDX2 expression stimulated by acid and bile salts in oesophageal squamous cells of patients with Barrett's oesophagus

AU - Huo, Xiaofang

AU - Zhang, Xi

AU - Yu, Chunhua

AU - Cheng, Edaire

AU - Zhang, Qiuyang

AU - Dunbar, Kerry B.

AU - Pham, Thai H.

AU - Lynch, John P.

AU - Wang, David H.

AU - Bresalier, Robert S.

AU - Spechler, Stuart J.

AU - Souza, Rhonda F.

PY - 2018/4/1

Y1 - 2018/4/1

N2 - 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-κ 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 Iκ B-NF-κ B-PKAc complex activation, p65 NF-κ 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 H 2 O 2, which activated the Iκ B-NF-κ B-PKAc complex. NES-B cells exhibited higher levels of phosphorylated Iκ B and p65 and greater NF-κ B transcriptional activity than NES-G cells, indicating greater Iκ B-NF-κ B-PKAc complex activation by acid and bile salts in NES-B cells, and p65 siRNA prevented their increased expression of CDX2. Aspirin blocked Iκ 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-κ 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.

AB - 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-κ 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 Iκ B-NF-κ B-PKAc complex activation, p65 NF-κ 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 H 2 O 2, which activated the Iκ B-NF-κ B-PKAc complex. NES-B cells exhibited higher levels of phosphorylated Iκ B and p65 and greater NF-κ B transcriptional activity than NES-G cells, indicating greater Iκ B-NF-κ B-PKAc complex activation by acid and bile salts in NES-B cells, and p65 siRNA prevented their increased expression of CDX2. Aspirin blocked Iκ 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-κ 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.

KW - INFLAMMATION

KW - OESOPHAGEAL DISEASE

KW - OESOPHAGEAL REFLUX

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UR - http://www.scopus.com/inward/citedby.url?scp=85044286815&partnerID=8YFLogxK

U2 - 10.1136/gutjnl-2016-313584

DO - 10.1136/gutjnl-2016-313584

M3 - Article

C2 - 28442495

AN - SCOPUS:85044286815

VL - 67

SP - 606

EP - 615

JO - Gut

JF - Gut

SN - 0017-5749

IS - 4

ER -