Interleukin-8 is the single most up-regulated gene in whole genome profiling of H. pylori exposed gastric epithelial cells

<p>Abstract</p> <p>Background</p> <p>The association between <it>Helicobacter pylori </it>infection and upper gastrointestinal disease is well established. However, only a small fraction of <it>H. pylori </it>carriers develop disease, and there are great geographical differences in disease penetrance. The explanation to this enigma lies in the interaction between the bacterium and the host. <it>H. pylori </it>Outer Membrane Phospholipase A (OMPLA) has been suggested to play a role in the virulence of this bacterium. The aim of this study was to profile the most significant cellular pathways and biological processes affected in gastric epithelial cells during 24 h of <it>H. pylori </it>exposure, and to study the inflammatory response to OMPLA⁺and OMPLA^-<it>H. pylori </it>variants.</p> <p>Results</p> <p>Interleukin-8 was the most significantly up-regulated gene and appears to play a paramount role in the epithelial cell response to <it>H. pylori </it>infection and in the pathological processes leading to gastric disease. MAPK and NF-kappaB cellular pathways were powerfully activated, but did not seem to explain the impressive <it>IL-8 </it>response. There was marked up-regulation of <it>TP53BP2</it>, whose corresponding protein ASPP2 may interact with <it>H. pylori </it>CagA and cause marked p53 suppression of apoptosis. Other regulators of apoptosis also showed abberant regulation. We also identified up-regulation of several oncogenes and down-regulation of tumor suppressor genes as early as during the first 24 h of infection. <it>H. pylori </it>OMPLA phase variation did not seem to influence the inflammatory epithelial cell gene response in this experiment.</p> <p>Conclusion</p> <p>In whole genome analysis of the epithelial response to <it>H. pylori </it>exposure, <it>IL-8 </it>demonstrated the most marked up-regulation, and was involved in many of the most important cellular response processes to the infection. There was dysregulation of apoptosis, tumor suppressor genes and oncogenes as early as in the first 24 h of <it>H. pylori </it>infection, which may represent early signs of gastric tumorigenesis. OMPLA^+/-did not affect the acute inflammatory response to <it>H. pylori</it>.</p

GFRA3 promoter methylation may be associated with decreased postoperative survival in gastric cancer

Background A large number of epigenetic alterations has been found to be implicated in the etiology of gastric cancer. We have studied the DNA methylation status of 27 500 gene promoter regions in 24 gastric adenocarcinomas from a Norwegian cohort, and aimed at identifying the hypermethylated regions. We have compared our findings to the gene expression in the same tissue, and linked our results to prognosis and survival. Methods Biopsies from gastric adenocarcinomas and adjacent normal gastric mucosa were obtained from 24 patients following surgical resection of the tumor. Genome-wide DNA methylation profiling of the tumor and matched non-cancerous mucosa was performed. The results were compared to whole transcriptome cDNA microarray analysis of the same material. Results Most of the gene promoter regions in both types of tissue showed a low degree of methylation, however there was a small, but significant hypermethylation of the tumors. Hierarchical clustering showed separate grouping of the tumor and normal tissue. Hypermethylation of the promoter region of the GFRA3 gene showed a strong correlation to post-operative survival and several of the clinicopathological parameters, however no difference was found between the two main histological types of gastric cancer. There was only a modest correlation between the DNA methylation status and gene expression. Conclusions The different DNA methylation clusters of the tumors and normal tissue indicate that aberrant DNA methylation is a distinct feature of gastric cancer, although there is little difference in the overall, and low, methylation levels between the two tissue types. The GFRA3 promoter region showed marked hypermethylation in almost all tumors, and its correlation with survival and other clinicopathological parameters may have important prognostic significance