{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T06:14:24Z","timestamp":1778134464993,"version":"3.51.4"},"reference-count":53,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2019,5,2]],"date-time":"2019-05-02T00:00:00Z","timestamp":1556755200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100008980","name":"Medical College of Wisconsin","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/100008980","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Laryngoscope"],"published-print":{"date-parts":[[2019,12]]},"abstract":"<jats:sec><jats:title>Objectives\/Hypothesis<\/jats:title><jats:p>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\u2010induced carcinogenic changes were assayed in an esophageal cell culture model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Study Design<\/jats:title><jats:p>Laboratory analysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>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\u2013polymerase chain reaction. The effect of pepsin on BE and EAC markers was investigated via enzyme\u2010linked immunosorbent assay and quantitative polymerase chain reaction in human esophageal epithelial cells treated with pepsin or control diluent.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>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\u2010free esophagi. Chronic pepsin treatment (0.1\u20131 mg\/mL, 4 weeks) of human esophageal cells in vitro induced BE and EAC markers interleukin 8 and<jats:italic>KRT8<\/jats:italic>and depleted normal esophageal marker<jats:italic>KRT10<\/jats:italic>(<jats:italic>P<\/jats:italic>&lt; .05) expression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>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\u2010attributed carcinogenic changes in the esophagus.<\/jats:p><\/jats:sec><jats:sec><jats:title>Level of Evidence<\/jats:title><jats:p>NA<jats:italic>Laryngoscope<\/jats:italic>, 129:2687\u20132695, 2019<\/jats:p><\/jats:sec>","DOI":"10.1002\/lary.28051","type":"journal-article","created":{"date-parts":[[2019,5,2]],"date-time":"2019-05-02T14:22:48Z","timestamp":1556806968000},"page":"2687-2695","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Esophageal pepsin and proton pump synthesis in barrett's esophagus and esophageal adenocarcinoma"],"prefix":"10.1002","volume":"129","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7045-357X","authenticated-orcid":false,"given":"Tina L.","family":"Samuels","sequence":"first","affiliation":[{"name":"Department of Otolaryngology and Communication Sciences 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Wisconsin"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander","family":"MacKinnon","sequence":"additional","affiliation":[{"name":"Department of Pathology Medical College of Wisconsin Milwaukee Wisconsin"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Catherine E.","family":"Hagen","sequence":"additional","affiliation":[{"name":"Department of Pathology Medical College of Wisconsin Milwaukee Wisconsin"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nikki","family":"Johnston","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology and Communication Sciences Medical College of Wisconsin Milwaukee Wisconsin"},{"name":"Department of Microbiology and Immunology Medical College of Wisconsin Milwaukee Wisconsin"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2019,5,2]]},"reference":[{"key":"e_1_2_7_2_1","article-title":"SEER Cancer Statistics Review, 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