Carcinogenesis Advance Access originally published online on August 19, 2005
Carcinogenesis 2006 27(2):319-327; doi:10.1093/carcin/bgi211
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Carcinogenesis vol.27 no.2 © Oxford University Press 2005; all rights reserved.
Low pH induces co-ordinate regulation of gene expression in oesophageal cells
1 Department of Clinical Medicine and 2 Department of Surgery, Institute of Molecular Medicine, Trinity Centre for Health Sciences, St James's Hospital, Dublin 8, Ireland and 3 Department of Pharmacology, Centre for Molecular Medicine, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin 4, Ireland
* To whom correspondence should be addressed. Tel: +353 1 6082100; Fax: +353 1 6083503; Email: spduggan{at}tcd.ie or kellehdp{at}tcd.ie
The development of gastro-oesophageal reflux disease (GORD) is known to be a causative risk factor in the evolution of adenocarcinoma of the oesophagus. 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. In more detail, oesophageal adenocarcinoma cell lines were exposed to a range of pH environments. Affymetrix microarrays were used for gene-expression analysis and results were validated using cycle limitation and real-time RT–PCR analysis, as well as northern and western blotting. Comparative promoter transcription factor binding site (TFBS) analysis (MatInspector) of hierarchically clustered gene-expression data was employed to identify the elements which may co-ordinately regulate individual gene clusters. Initial experiments demonstrated maximal induction of EGR1 gene expression at pH 6.5. Subsequent array experimentation revealed significant induction of gene expression from such functional categories as DNA damage response (EGR1-4, ATF3) and cell-cycle control (GADD34, GADD45, p57). Changes in expression of EGR1, EGR3, ATF3, MKP-1, FOSB, CTGF and CYR61 were verified in separate experiments and in a variety of oesophageal cell lines. TFBS analysis of promoters identified transcription factors that may co-ordinately 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 functional analysis of the 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.
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