title: Proinflammatory cytokines and bile acids upregulate ΔNp73 protein, an inhibitor of p53 and p73 tumor suppressors.
abstract: 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, ΔNp73α, in the reflux condition. Previous studies have reported that ΔNp73 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 ΔNp73, its subcellular localization and increases ΔNp73 protein levels. Upregulation of ΔNp73 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 ΔNp73. Their inhibition with chemotherapeutic agents and siRNA suppresses ΔNp73. We also found that pro-inflammatory cytokines, IL-1β and TNFα, are potent inducers of ΔNp73α, which further enhance the bile acids/acid effect. Combined, our studies provide evidence that gastroesophageal reflux alters the regulation of oncogenic ΔNp73 isoform that may facilitate tumorigenic transformation of esophageal metaplastic epithelium.
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, United States of America.
authors.forename: Elena
authors.initials: E
authors.lastname: Zaika
authors.forename: Vikas
authors.initials: V
authors.lastname: Bhardwaj
authors.forename: Jinxiong
authors.initials: J
authors.lastname: Wei
authors.forename: Mary Kay
authors.initials: MK
authors.lastname: Washington
authors.forename: Rhonda
authors.initials: R
authors.lastname: Souza
authors.forename: Wael
authors.initials: W
authors.lastname: El-Rifai
authors.forename: Alexander
authors.initials: A
authors.lastname: Zaika
mesh_terms: D001483:Base Sequence; D001647:Bile Acids and Salts / Q000502:physiology*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000502:physiology*; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D005764:Gastroesophageal Reflux / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000502:physiology*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors*; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology*
chemical_list: D001647:Bile Acids and Salts; D016207:Cytokines; D017931:DNA Primers; D004268:DNA-Binding Proteins; D018836:Inflammation Mediators; D009687:Nuclear Proteins; C495901:TP53 protein, human; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C000606369:delta Np73 protein, human