title: Local Synthesis of Pepsin in Barrett's Esophagus and the Role of Pepsin in Esophageal Adenocarcinoma.
abstract: OBJECTIVE
  Despite widespread use of proton pump inhibitors (PPIs), the incidence of esophageal adenocarcinoma (EAC) continues to rise. PPIs reduce reflux acidity, but only transiently inactivate gastric enzymes. Nonacid reflux, specifically nonacid pepsin, contributes to carcinogenesis in the larynx. Given the carcinogenic potential of pepsin and inefficacy of PPIs to prevent EAC, the presence and effect of pepsin in the esophagus should be investigated.
  
  
  METHODS
  Normal and Barrett's biopsies from 8 Barrett's esophagus patients were collected for pepsin analysis via Western blot and reverse transcriptase-polymerase chain reaction (RT-PCR). Human esophageal cells cultured from healthy patients were treated with pepsin (0.01-1 mg/mL; 1-20 hours), acid (pH 4)±pepsin (5 minutes); real-time RT-PCR, ELISA, and cell migration were assayed.
  
  
  RESULTS
  Pepsin was detected in all 8 Barrett's and 4 of 8 adjacent normal specimens. Pepsinogen mRNA was observed in 22 Barrett's, but not in normal adjacent samples. Pepsin induced PTSG2 (COX-2) and IL-1β expression and cell migration in vitro.
  
  
  CONCLUSIONS
  Pepsin is synthesized by metaplastic, Barrett's esophageal mucosa. Nonacid pepsin increases metrics of tumorigenicity in esophageal epithelial cells in vitro. These findings implicate refluxed and locally synthesized pepsin in development and progression of EAC and, in part, explain the inefficacy of PPIs in the prevention of EAC.
authors.affiliation: Department of Otolaryngology and Communication Sciences, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Tina
authors.initials: T
authors.lastname: Samuels
authors.affiliation: Department of Otolaryngology and Communication Sciences, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Craig
authors.initials: C
authors.lastname: Hoekzema
authors.affiliation: Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Jon
authors.initials: J
authors.lastname: Gould
authors.affiliation: Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Goldblatt
authors.affiliation: Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Frelich
authors.affiliation: Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Bosler
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Sang-Hyuk
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Department of Otolaryngology and Communication Sciences, Medical College of Wisconsin, Milwaukee, Wisconsin, USA njohnston@mcw.edu.
authors.forename: Nikki
authors.initials: N
authors.lastname: Johnston
mesh_terms: D000230:Adenocarcinoma / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D001471:Barrett Esophagus / Q000378:metabolism / Q000473:pathology; D063646:Carcinogenesis / Q000378:metabolism; D054443:Cell Migration Assays / Q000379:methods; D002478:Cells, Cultured; D018450:Disease Progression; D004938:Esophageal Neoplasms / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D004947:Esophagus / Q000378:metabolism / Q000473:pathology; D005764:Gastroesophageal Reflux / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D010434:Pepsin A / Q000096:biosynthesis*; D054328:Proton Pump Inhibitors / Q000494:pharmacology*
chemical_list: D053583:Interleukin-1beta; D054328:Proton Pump Inhibitors; D010434:Pepsin A
keywords: Barrett’s esophagus; adenocarcinoma of esophagus; gastroesophageal reflux; pepsin; proton pump inhibitors; reflux