Upregulation of the oncogene c-myc in Barrett's adenocarcinoma: induction of c-myc by acidified bile acid in vitro |
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Authors: | Tselepis C Morris C D Wakelin D Hardy R Perry I Luong Q T Harper E Harrison R Attwood S E A Jankowski J A Z |
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Affiliation: | Epithelial Laboratory, Division of Medical Sciences, University of Birmingham, UK. christi@cancer.bham.ac.uk |
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Abstract: | BACKGROUND AND AIMS: 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. |
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