Tselepis, C.; Sharma, N.; Hardy, R.
April 2003
Gut;Apr2003 Supplement 1, Vol. 52, pA36
Academic Journal
Barrett's metaplasia is a premalignant lesion predisposing to oesophageal adenocarcinoma. Patients with Barrett's metaplasia have an approximate 0.5-2% annual risk of developing adenocarcinoma, 30-125 times the risk seen in the general population. Barrett's metaplasia is associated with severe gastro-oesophageal reflux disease and there is increasing evidence that the reflux of bile acids is likely to be important in malignant development. We have previously demonstrated that c-Myc is upregulated in the malignant progression of Barrett's metaplasia, and using in vitro cell models shown that bile acids can induce c-Myc. However, because c-Myc alone is unable to transactivate genes associated with mitogenic and oncogenic functions we sought to characterise the other essential c-Myc network proteins, namely Mad-1 and Max in this malignant process. By use of microarrays on RNA extracted from Barrett's metaplasia (n = 4) we have identified the c-Myc antagonist Mad-1 as downregubred. These data were verified by quantitative real time PCR and have shown that in 19/20 Barrett's metaplasia samples there was Mad-1 repression. By Western blotting we were able to demonstrate that repression also occurred at the level of protein. Furthermore, Mad-1 expression was also modulated in cell culture experiments. Thus our data would suggest that in the malignant progression of this disease an imbalance in the c-Myc regulatory system exists, with c-Myc being over-expressed while the c-Myc antagonist Mad-1 repressed. Furthermore, with increasing evidence that components of the refluxate can modulate these proteins this may provide a useful tool for identifying Barrett's patients at greatest risk of developing adenocarcinoma, leading to an impact on surveillance programmes and patient healthcare.


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