Carcinogenesis Advance Access published online on August 19, 2005
Carcinogenesis, doi:10.1093/carcin/bgi211
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1 Department of Clinical Medicine, Institute of Molecular Medicine, Trinity Centre for Health sciences, St James's Hospital, Dublin 8, Ireland
* To whom correspondence should be addressed. The development of gastro-oesophageal reflux disease (GORD) is known to be a causative risk factor in the evolution of adenocarcinoma of the esophagus. The major component of this reflux is gastric acid, however the impact of low pH on gene expression has not been extensively studied in oesophageal cells. This study utilizes a transcriptomic and bioinformatic approach to assess regulation of gene expression in response to low pH. The oesophageal adenocarcinoma cell lines were exposed to a range of low pH environments. Affymetrix microarrays were used for expression analysis and results were validated using RT-PCR, Real Time-RT-PCR, Northern and Western blotting. Bioinformatic analysis using Genespring and Coordinate promoter transcription factor binding site analysis (MatInspector) of hierarchically clustered data was employed to identify regulatory elements of individual clusters. Initial experiments demonstrated maximal induction of EGR1 gene expression at pH6.5. Subsequent array experimentation revealed significant induction of gene expression from such functional categories as DNA damage response (Egr-1-4, ATF3) and cell cycle control (GADD34, 45, p57). Changes in expression of EGR1, EGR3, ATF3, MKP-1, FOSB, CTGF and CYR61 have been verified in separate experiments and in a variety of oesophageal cell lines. Transcription factor binding site analysis of promoters, identified transcription factors that coordinately regulate gene expression clusters, Cluster 1:- Oct-1, AP4R Cluster 2:- NF-kB, EGRF, Cluster 3:- IKRS, AP-1F. Low pH has the ability to induce genes and pathways which can provide an environment suitable for the progression of malignancy. Further analysis of the functional roles of genes and clusters identified in this low pH study is likely to lead to new insights into the pathogenesis and therapeutics of GORD and oesophageal cancer.
Received January 13, 2005
Revised August 9, 2005
Accepted August 12, 2005
CARCINOGENESIS
Low pH results in coordinate regulation of gene expression in oesophageal cells
2 Department of pharmacology, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin 4, Ireland
Shane Duggan, E-mail: spduggan{at}tcd.ie
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