Tina Samuels1, Craig Hoekzema1, Jon Gould2, Matthew Goldblatt2, Matthew Frelich2, Matthew Bosler2, Sang-Hyuk Lee3, Nikki Johnston4. 1. Department of Otolaryngology and Communication Sciences, Medical College of Wisconsin, Milwaukee, Wisconsin, USA. 2. Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin, USA. 3. Department of Otorhinolaryngology-Head and Neck Surgery, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea. 4. Department of Otolaryngology and Communication Sciences, Medical College of Wisconsin, Milwaukee, Wisconsin, USA njohnston@mcw.edu.
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.
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: S E Axford; N Sharp; P E Ross; J P Pearson; P W Dettmar; M Panetti; J A Koufman Journal: Ann Otol Rhinol Laryngol Date: 2001-12 Impact factor: 1.547
Authors: G Pals; A W Eriksson; J C Pronk; R R Frants; E C Klinkenberg-Knol; A Bosma; B D Westerveld; R T Taggart; I M Samloff; S G Meuwissen Journal: Clin Genet Date: 1988-08 Impact factor: 4.438
Authors: Baljeet S Kaur; Niloufar Khamnehei; Mohamed Iravani; Sai S Namburu; Otto Lin; George Triadafilopoulos Journal: Gastroenterology Date: 2002-07 Impact factor: 22.682
Authors: Nikki Johnston; Justin C Yan; Craig R Hoekzema; Tina L Samuels; Gary D Stoner; Joel H Blumin; Jonathan M Bock Journal: Laryngoscope Date: 2012-05-08 Impact factor: 3.325