Background
In esophageal adenocarcinoma, MUC1 mucin expression increases in early stages of the
carcinogenetic sequence, during which bile reflux has been identified as a major carcinogen.
However, no link between MUC1 overexpression and the presence of bile acids in the
reflux has been established so far, and molecular mechanisms regulating MUC1 expression
during esophageal carcinogenetic sequence are unknown. Our aim was to identify (1)
the bile acids able to upregulate MUC1 expression in esophageal cancer cells and mucosal
samples, (2) the regulatory regions in MUC1 promoter responsive to bile acids, and
(3) the signaling pathway(s) involved in this regulation.
Methods
MUC1 mRNA and mucin expression were studied by the means of real-time reverse transcriptase
polymerase chain reaction (RT-PCR) and immunohistochemistry, both in the human esophageal
OE33 adenocarcinoma cell line and in an ex vivo explant model. MUC1 promoter was cloned
and transcription regulation was studied by transient cell transfection to identify
the bile acid–responsive regions. Signaling pathways involved were identified using
specific pharmacologic inhibitors and siRNA approach.
Results
Taurocholic, taurodeoxycholic, taurochenodeoxycholic, glycocholic, sodium glycocholate,
and deoxycholic bile acids upregulated MUC1 mRNA and protein expression. The highest
induction was obtained with deoxycholic and taurocholic acids in both cellular and
explant models. The bile acid–mediated upregulation of MUC1 transcription occurs at
the promoter level, with responsive elements located in the -1472/-234 region of the
promoter, and involves the phosphatidylinositol 3-kinase signaling pathway.
Conclusions
Bile acids induce MUC1 mucin overexpression in human esophageal adenocarcinoma cells
and tissues by activating its transcription through a process involving phosphatidylinositol
3-kinase.
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Article info
Publication history
Accepted:
July 10,
2007
Footnotes
Supported by a grant from le Comité du Pas-de-Calais de la Ligue Nationale contre le Cancer (I.V.S.).
The first two authors contributed equally to this publication.
Identification
Copyright
© 2008 Mosby, Inc. Published by Elsevier Inc. All rights reserved.
