Bile acids (BAs) arising from duodenogastric reflux are known to facilitate gastric cancer (GC) development. Although BAs traditionally contribute to carcinogenesis through direct cellular cytotoxicity, increasing evidence implicates nuclear and membrane BA receptors (BARs) as additional factors influencing cancer risk. Indeed, some BARs are already linked with GC, but conflicting evidence and lack of information regarding other endogenous BARs warrant further investigation. In this study, we meta-analyzed multiple data sets to identify clinically relevant relationships between BAR expression and prognosis, clinicopathology, and activity in GC.

We collected transcriptomic data from the Gene Expression Omnibus and The Cancer Genome Atlas to analyze associations between BAR expression and GC prognosis, subtype, and clinicopathology. We also used Ingenuity Pathway Analysis to assess and predict functions, upstream regulators, and downstream mediators of membrane and nuclear BARs in GC.

BARs showed differential distribution in GC; membrane BARs (G protein-coupled BAR 1, sphingosine-1-phosphate receptor 2, and cholinergic receptor muscarinic 2) were enriched in diffuse-, genome-stable, and mesenchymal-type tumors, whereas nuclear BARs (pregnane-X-receptor, constitutive androstane receptor, and farnesoid-X-receptor) were enriched in chromosome instability and metabolic subtypes. High expression of all membrane but not nuclear BARs was associated with poor prognosis and unfavorable GC clinicopathologic features. Similarly, expression patterns of membrane but not nuclear BARs varied geographically, aligning with Helicobacter pylori infection and GC mortality rates. Finally, GC-related oncogenes, namely transforming growth factor β1, were associated with membrane BARs, whereas many metabolic-associated genes were associated with nuclear BARs.

Through transcriptomic meta-analysis, we identified distinct expression profiles between nuclear and membrane BARs that demonstrate prognostic relevance and warrant further investigation.

Helicobacter pylori is a gastric pathogen that colonizes approximately 50% of the world's population. Infection with H. pylori causes chronic inflammation and significantly increases the risk of developing duodenal and gastric ulcer disease and gastric cancer. Infection with H. pylori is the strongest known risk factor for gastric cancer, which is the second leading cause of cancer-related deaths worldwide. Once H. pylori colonizes the gastric environment, it persists for the lifetime of the host, suggesting that the host immune response is ineffective in clearing this bacterium. In this review, we discuss the host immune response and examine other host factors that increase the pathogenic potential of this bacterium, including host polymorphisms, alterations to the apical-junctional complex, and the effects of environmental factors. In addition to host effects and responses, H. pylori strains are genetically diverse. We discuss the main virulence determinants in H. pylori strains and the correlation between these and the diverse clinical outcomes following H. pylori infection. Since H. pylori inhibits the gastric epithelium of half of the world, it is crucial that we continue to gain understanding of host and microbial factors that increase the risk of developing more severe clinical outcomes.

Helicobacter pylori infection of the gastric mucosa is strongly associated with gastritis, peptic ulcer disease, and gastric cancer. However, the mechanisms by which H. pylori causes cancer are currently unknown. Binding of epidermal growth factor (EGF) to its receptor (EGFR) may be important in the development of gastric cancer. This interaction accelerates cell proliferation and migration, and triggers epithelial cell signaling. In this study, we investigated the effects of H. pylori on EGFR- and AP-1-mediated signal transduction pathways in the AGS gastric epithelial cell line and gastric tissue from humans.

Cells were treated with H. pylori and cell death was examined at a variety of time points using cell viability and trypan blue exclusion dye assay. To investigate the effects on EGFR regulation, AGS cells were transfected with a full-length and truncated EGFR luciferase (luc) reporter. Tissue microarray containing 44 samples of gastric biopsies from H. pylori-positive patients was analyzed for protein expression level of EGFR by immunohistochemistry.

EGFR promoter activity was increased (twofold) 3 h after treatment with H. pylori commenced. Using a series of EGFR promoter deletion mutants, we identified a region that was crucial for transactivation of the EGFR by H. pylori. To determine whether AP-1 binding was altered, we transfected AGS cells with an AP-1 luciferase construct and then treated them with H. pylori for up to 6 h. We found that AP-1 activity was induced by H. pylori in gastric cells, while electrophoretic mobility shift assays confirmed that binding of AP-1 to the EGFR promoter site was increased following H. pylori treatment. Binding of c-Jun and c-Fos to the EGFR promoter region -1,062/-900 was induced eight- and six fold, respectively, using ChIP assay. Active EGFR staining was markedly increased in gastric mucosa from infected persons, compared to uninfected controls.

We conclude that exposure of gastric cells to H. pylori induces increased production of EGFR through various signal transduction pathways, including those mediated by the EGFR and AP-1. Distinct effects on EGFR activation may specify the subset of AP-1 target genes that are selected, including those involved in proliferation and apoptosis. This is consistent with EGFR activation that was found in the gastric mucosa of humans infected with H. pylori. Hence, the balance between apoptosis and proliferation in these cells may be altered in response to injury caused by H. pylori infection, leading to an increased risk of cancer.

To study the effect of proton pump inhibitor (PPI) treatment on patients with reflux esophagitis and its in vivo effect on apoptosis, p53- and epidermal growth factor receptor (EGFR) expression.

After informed consent was obtained, gastric biopsies of the antrum were taken from patients with reflux oesophagitis prior to and after 6 mo of 20 mg omeprazole (n = 14) or 40 mg esomeprazole (n = 12) therapy. Patients did not take any other medications known to affect the gastric mucosa. All patients were Helicobacter pylori negative as confirmed by rapid urease test and histology, respectively. Cell proliferation, apoptosis, EGFR, and p53 expression were measured by immunohistochemical techniques. At least 600 glandular epithelial cells were encountered and results were expressed as percentage of total cells counted. Was considered statistically significant.

Although there was a trend towards increase of cell proliferation and EGFR expression both in omeprazole and esomeprazole treated group, the difference was not statistically significant. Neither apoptosis nor p53 expression was affected.

Long-term PPI treatment does not significantly increase gastric epithelial cell proliferation and EGFR expression and has no effect on apoptosis and p53 expression.

Proton pump inhibitor (PPI) co-therapy is considered the best strategy in preventing gastrointestinal complications during non-steroidal anti-inflammatory drug (NSAID) treatment, but there is limited information available on its effect on gastric mucosal cell kinetics. To evaluate the effect of PPI co-therapy on gastric mucosa we investigated epithelial cell proliferation, apoptosis, epithelial growth factor receptor (EGFR) and p53 expression in patients on chronic non-selective NSAID or cyclooxygenase-2 selective inhibitor (COX-2) treatment. Gastric biopsies of the antrum were taken from 10-10 patients on chronic NSAID and COX-2, therapy prior and after 6 months PPI co-therapy, and 10 controls without any treatment. Cell proliferation, apoptosis, EGFR and p53 expression were measured by immunohistochemistry. At least 600 glandular epithel cells were encountered and results were expressed as % of total cells counted. We found increased cell proliferation in patients on chronic COX-2 but not on NSAID therapy. Patients on either NSAID or COX-2 therapy had an increased p53 and decreased EGFR expression. PPI therapy reversed not only the increased cell proliferation and p53 expression, but also the suppressed EGFR expression when administered as co-therapy. The fewer gastrointestinal side effects observed during chronic COX-2 therapy may partially be the result of the higher cell proliferation. This effect is not mediated by the EGFR pathway. PPI co-therapy normalizes the disturbed cell kinetics irrespective of NSAID treatment used.