Loading...
The combination of gastroesophageal reflux disease and Barrett esophagus (BE) is a risk factor for esophageal adenocarcinoma. Although this association is well established, the mechanism by which acid reflux can accelerate progression from BE to cancer has not been established. One hypothesis is that reactive oxygen species (ROS) mitigate acid-induced neoplastic changes by facilitating genetic mutations and altering functions of enzymes and proteins (e.g., oncogenes, tumor-suppressor proteins). Low levels of ROS are thought to be by-products of aerobic metabolism, but high levels of ROS are found in both BE and esophageal adenocarcinoma cells. Several superoxide-generating homologues have been identified that can affect cell function relative to immunity, signal transduction, and modification of the cellular matrix. An isoform of the nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase catalytic subunit NOX5 is the major species present in esophageal adenocarcinoma cells.
Researchers exposed cultured human esophageal squamous cells and BE adenocarcinoma cells to pulsed acidic conditions to evaluate whether NOX5 contributed to the formation of acid-induced ROS. NOX5 was upregulated significantly by acid in both cells types; levels of acid-induced NOX5 expression were significantly higher at pH 4.0 than at pH 7.2 (P<0.01). Knockdown (using small interfering RNAs) of NOX5 significantly decreased thymidine incorporation (a measure of accelerated proliferative activity), decreased retinoblastoma protein phosphorylation, and increased cell apoptosis. In biopsy samples from BE patients, levels of NOX5 were significantly higher in BE tissues with high-grade dysplasia than in those without dysplasia.
Fu X et al. cAMP-response element-binding protein mediates acid-induced NADPH oxidase NOX5-S expression in Barrett esophageal adenocarcinoma cells. J Biol Chem 2006 Jul 21; 281:20368-82.
Comment
These findings demonstrate that acid facilitates expression of the NADPH-oxidase subunit NOX5. This sequence appears to be associated with increased proliferative patterns and reduced apoptosis. This mediator also has been apparent in other cancers (e.g., melanoma, prostate cancer). To date, aggressive acid suppression has been used to control symptoms in BE patients; in vitro data have suggested that acid has a role in changing proliferative patterns, increasing cellular differentiation, and upregulating cyclooxygenase-2 expression (Journal Watch Gastroenterology Jul 1 2000), all of which might be involved in progression to neoplasia. These findings highlight yet another reason to employ potent acid suppression in BE patients. Clearly, prospective studies are required, and such trials should focus on finding the optimal level of acid suppression to interact most favorably with these intermediate markers — which we hope will correlate, in the long term, with prevention of esophageal cancer.