Upregulation of the oncogene c-myc in Barrett's adenocarcinoma: induction of c-myc by acidified bile acid in vitro.
OBJECTIVE
C-myc over expression is implicated in malignancy although to date this has not been studied in Barrett's metaplasia. We sought to determine c-myc expression in the malignant progression of Barrett's metaplasia and whether it may be induced by bile acids seen in gastro-oesophageal refluxate.


METHODS
C-myc protein and mRNA levels were assessed in 20 Barrett's metaplasia and 20 oesophageal adenocarcinoma samples by western blotting and real time polymerase chain reaction. Levels of c-myc and proliferation were also assessed in cell lines OE21, OE33, SW-480, and TE-7 stimulated with pulses or continuous exposure to the bile acids deoxycholic acid and chenodeoxycholic acid.


RESULTS
C-myc protein was upregulated in 50% of Barrett's metaplasia and 90% of oesophageal adenocarcinoma samples compared with squamous, gastric, and duodenal controls. C-myc immunolocalisation in Barrett's metaplasia revealed discrete nuclear localisation, becoming more diffuse with progression from low to high grade dysplasia to adenocarcinoma. Both continual and pulsed bile acid induced c-myc at pH 4, with no effect at pH 7 or with acidified media alone. Pulsed bile acid treatment induced proliferation (p<0.05); in contrast, continuous exposure led to suppression of proliferation (p<0.05).


CONCLUSIONS
We have shown upregulation of c-myc with malignant progression of Barrett's metaplasia and suggest that acidified bile may be a novel agent responsible for induction of this oncogene.
Tselepis
C
C
Epithelial Laboratory, Division of Medical Sciences, University of Birmingham, UK. christi@cancer.bham.ac.uk
Morris
C D
CD
Wakelin
D
D
Hardy
R
R
Perry
I
I
Luong
Q T
QT
Harper
E
E
Harrison
R
R
Attwood
S E A
SE
Jankowski
J A Z
JA
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D001471:Barrett Esophagus / Q000235:genetics* / Q000473:pathology; D001647:Bile Acids and Salts / Q000494:pharmacology*; D015153:Blotting, Western / Q000379:methods; D002455:Cell Division; D002635:Chenodeoxycholic Acid / Q000494:pharmacology; D003840:Deoxycholic Acid / Q000494:pharmacology; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000473:pathology; D005455:Fluorescent Antibody Technique / Q000379:methods; D005764:Gastroesophageal Reflux / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D016259:Genes, myc / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D016133:Polymerase Chain Reaction / Q000379:methods; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects* / Q000235:genetics
D001647:Bile Acids and Salts; D003840:Deoxycholic Acid; D002635:Chenodeoxycholic Acid