Proinflammatory Cytokines and Bile Acids Upregulate ΔNp73 Protein, an Inhibitor of p53 and p73 Tumor Suppressors

Gastroesophageal reflux disease (GERD) is the main etiological factor behind the recent rapid increase in the incidence of esophageal adenocarcinoma. During reflux, esophageal cells are exposed to bile at low pH resulting in cellular damage and inflammation, which are known to facilitate cancer development. In this study, we investigated the regulation of p73 isoform, Delta Np73 alpha, in the reflux condition. Previous studies have reported that Delta Np73 exhibits anti-apoptotic and oncogenic properties through inhibition of p53 and p73 proteins. We found that direct exposure of esophageal cells to bile acids in an acidic environment alters the phosphorylation of Delta Np73, its subcellular localization and increases Delta Np73 protein levels. Upregulation of Delta Np73 was also observed in esophageal tissues collected from patients with GERD and Barrett's metaplasia, a precancerous lesion in the esophagus associated with gastric reflux. c-Abl, p38 MAPK, and IKK protein kinases were identified to interact in the regulation of Delta Np73. Their inhibition with chemotherapeutic agents and siRNA suppresses Delta Np73. We also found that pro-inflammatory cytokines, IL-1 beta and TNF alpha, are potent inducers of Delta Np73 alpha, which further enhance the bile acids/acid effect. Combined, our studies provide evidence that gastroesophageal reflux alters the regulation of oncogenic Delta Np73 isoform that may facilitate tumorigenic transformation of esophageal metaplastic epithelium.