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Esophageal pepsin and proton pump synthesis in barrett's esophagus and esophageal adenocarcinoma. Laryngoscope 2019 12;129(12):2687-2695



Pubmed ID




Scopus ID

2-s2.0-85065403373   4 Citations


OBJECTIVES/HYPOTHESIS: Gastroesophageal reflux disease and associated metaplasia of the esophagus (Barrett's esophagus [BE]) are primary risk factors for esophageal adenocarcinoma (EAC). Widespread use of acid suppression medications has failed to stem the rise of EAC, suggesting that nonacid reflux may underlie its pathophysiology. Pepsin is a tumor promoter in the larynx and has been implicated in esophageal carcinogenesis. Herein, specimens from the esophageal cancer spectrum were tested for pepsin presence. Pepsin-induced carcinogenic changes were assayed in an esophageal cell culture model.

STUDY DESIGN: Laboratory analysis.

METHODS: Pepsin was assayed in reflux and cancer free esophagi, BE, EAC, and esophageal cancer lacking association with reflux (squamous cell carcinoma [SCC]). Refluxed or locally synthesized pepsin was assayed by Western blot. Local synthesis of pepsin and proton pumps was assayed via reverse transcription-polymerase chain reaction. The effect of pepsin on BE and EAC markers was investigated via enzyme-linked immunosorbent assay and quantitative polymerase chain reaction in human esophageal epithelial cells treated with pepsin or control diluent.

RESULTS: Pepsinogen and proton pump mRNA were observed in BE (3/5) and EAC (4/4) samples, but not in normal adjacent specimens, SCC (0/2), or reflux and cancer-free esophagi. Chronic pepsin treatment (0.1-1 mg/mL, 4 weeks) of human esophageal cells in vitro induced BE and EAC markers interleukin 8 and KRT8 and depleted normal esophageal marker KRT10 (P < .05) expression.

CONCLUSIONS: Local synthesis of pepsin and proton pumps in BE and EAC is not uncommon. Absence of these molecules in normal (noncancer) esophagi, SCC, and in vitro data support a role for pepsin in reflux-attributed carcinogenic changes in the esophagus.

LEVEL OF EVIDENCE: NA Laryngoscope, 129:2687-2695, 2019.

Author List

Samuels TL, Altman KW, Gould JC, Kindel T, Bosler M, MacKinnon A, Hagen CE, Johnston N


Jon Gould MD Chief, Professor in the Surgery department at Medical College of Wisconsin
Nikki Johnston PhD Associate Professor in the Otolaryngology department at Medical College of Wisconsin
Tammy Lyn Kindel MD, PhD Associate Professor in the Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Barrett Esophagus
Biomarkers, Tumor
Disease Progression
Esophageal Neoplasms
Follow-Up Studies
Gene Expression Regulation, Neoplastic
Pepsin A
Proton Pumps
RNA, Neoplasm
Retrospective Studies
Risk Factors
Tumor Cells, Cultured
jenkins-FCD Prod-480 9a4deaf152b0b06dd18151814fff2e18f6c05280