Abstract
Background
Nuclear factor-kappaB (NF-κB) regulates the expression of a large number of genes
involved in the immune and inflammatory response. NF-κB is constitutively activated
in oesophageal tumour tissues and induced in oesophageal cells by bile and acid. The
aim of the present study was to define the mechanisms underlying NF-κB activation
in oesophageal adenocarcinoma.
Patients and methods
Fresh biopsy specimens were obtained from 20 patients with oesophageal adenocarcinoma.
The activation of NF-κB in oesophageal tumour specimens and oesophageal SKGT-4 cells
was assessed by gel mobility shift and Western blotting. Phosphorylation of protein
kinase B (AKT/PKB), Ikappa kinase-alpha/beta (IKK-α/β) and extracellular signal-regulated
kinase 1/2 (ERK1/2) was examined by Western blotting. High content analysis was used
to quantify NF-κB translocation in oesophageal cells.
Results
Oesophageal tumour tissues had higher levels of NF-κB. Increased levels of phosphorylated
AKT and IKK-α/β and ERK1/2 were detected in tumour tissues compared with normal oesophageal
mucosa. Exposure of SKGT-4 cells to deoxycholic acid (DCA) or acid resulted in NF-κB
activation and phosphorylation of AKT, IKK-α/β and ERK1/2. Specific inhibitors for
phosphoinositide 3-kinase; PI3K (LY294002 and worhmannin) and ERK1/2 inhibitors (PD98059
and U0126) suppressed DCA- and acid-induced NF-κB activation. The proteasome inhibitor
MG-132 and the antioxidants vitamin C and pyrrolidine dithiocarbamate (PDTC) also
inhibited NF-κB activation.
Conclusions
Our data demonstrate a major role for PI3K/AKT–IKK-α/β–ERK1/2 signalling pathway in
NF-κB activation in oesophageal adenocarcinoma. These results suggest that NF-κB may
be a prognostic marker for oesophageal adenocarcinoma, and modulating of NF-κB may
uncover new therapeutic strategies.
Keywords
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Article info
Publication history
Published online: January 14, 2015
Accepted:
November 16,
2014
Received in revised form:
November 13,
2014
Received:
May 15,
2014
Identification
Copyright
© 2015 Published by Elsevier Inc.
