{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T13:04:54Z","timestamp":1792674294339,"version":"4.5.0"},"reference-count":45,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2012,5,8]],"date-time":"2012-05-08T00:00:00Z","timestamp":1336435200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Laryngoscope"],"published-print":{"date-parts":[[2012,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective\/Hypothesis:<\/jats:title><jats:p>Laryngopharyngeal reflux (LPR) is thought to be a significant risk factor for laryngeal squamous cell carcinoma (SCC), but causality has never been proven. It is accepted that chronic reflux into the esophagus can induce metaplastic changes in esophageal mucosa with subsequent increased risk of esophageal adenocarcinoma, but no similar associations have been established for LPR and laryngopharyngeal SCC. The objective of this study was to test the hypothesis that reflux of pepsin into the laryngopharynx can promote carcinogenesis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Study Design:<\/jats:title><jats:p>Translational research study.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods:<\/jats:title><jats:p>Normal human laryngeal primary epithelial cell cultures and hypopharyngeal FaDu SCC cells were exposed to human pepsin and analyzed by Human Cancer PathwayFinder and miRNA Superarrays, flow cytometry, and Western blot to determine the effect of pepsin on carcinogenesis. Laryngeal biopsy specimens taken from cancer patients and normal control subjects were analyzed for the presence of pepsin by Western blot.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results:<\/jats:title><jats:p>Microarray analysis demonstrated that pepsin significantly altered the expression of 27 genes implicated in carcinogenesis and also affected the expression of 22 microRNAs known to be altered in human head and neck cancers. Pepsin increased proliferation in both FaDu SCC cells and cultured normal laryngeal epithelial primary cells by increasing S phase distribution on flow cytometry analysis in a time\u2010 and dose\u2010dependent manner. Furthermore, pepsin was detected in 60% (3\/5) human laryngeal cancer biopsies, absent in all (0\/5) normal control specimens.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions:<\/jats:title><jats:p>These data support a role for refluxed pepsin in the promotion of epithelial proliferation and carcinogenesis of the larynx and pharynx. Laryngoscope, 2012<\/jats:p><\/jats:sec>","DOI":"10.1002\/lary.23307","type":"journal-article","created":{"date-parts":[[2012,3,23]],"date-time":"2012-03-23T11:33:08Z","timestamp":1332502388000},"page":"1317-1325","source":"Crossref","is-referenced-by-count":102,"title":["Pepsin promotes proliferation of laryngeal and pharyngeal epithelial cells"],"prefix":"10.1002","volume":"122","author":[{"given":"Nikki","family":"Johnston","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin C.","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig R.","family":"Hoekzema","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tina L.","family":"Samuels","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary D.","family":"Stoner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joel H.","family":"Blumin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan M.","family":"Bock","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2012,5,8]]},"reference":[{"key":"e_1_2_6_2_2","doi-asserted-by":"publisher","DOI":"10.3322\/canjclin.55.1.10"},{"key":"e_1_2_6_3_2","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.epirev.a036223"},{"key":"e_1_2_6_4_2","volume-title":"Cancer Facts and Figures 2011","author":"American Cancer Society","year":"2011"},{"key":"e_1_2_6_5_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-0-387-88441-7_5"},{"key":"e_1_2_6_6_2","doi-asserted-by":"publisher","DOI":"10.1097\/00020840-200204000-00006"},{"key":"e_1_2_6_7_2","first-page":"51","article-title":"High incidence of high\u2010risk HPV in benign and malignant lesions of the larynx","volume":"39","author":"Duray A","year":"2011","journal-title":"Int J Oncol"},{"key":"e_1_2_6_8_2","doi-asserted-by":"publisher","DOI":"10.1002\/lary.1991.101.s53.1"},{"key":"e_1_2_6_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcv.2004.11.017"},{"key":"e_1_2_6_10_2","doi-asserted-by":"publisher","DOI":"10.1097\/00005537-200006000-00023"},{"key":"e_1_2_6_11_2","doi-asserted-by":"publisher","DOI":"10.1017\/S0022215100056693"},{"key":"e_1_2_6_12_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1572-0241.2001.03934.x"},{"key":"e_1_2_6_13_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF00456363"},{"key":"e_1_2_6_14_2","doi-asserted-by":"publisher","DOI":"10.1177\/019459988809900403"},{"key":"e_1_2_6_15_2","doi-asserted-by":"publisher","DOI":"10.1288\/00005537-198811000-00009"},{"key":"e_1_2_6_16_2","doi-asserted-by":"publisher","DOI":"10.1177\/000348940711600613"},{"key":"e_1_2_6_17_2","doi-asserted-by":"publisher","DOI":"10.1097\/00005537-200306000-00027"},{"key":"e_1_2_6_18_2","doi-asserted-by":"publisher","DOI":"10.1097\/01.sla.0000143244.76135.ca"},{"key":"e_1_2_6_19_2","doi-asserted-by":"publisher","DOI":"10.1001\/archsurg.138.7.751"},{"key":"e_1_2_6_20_2","doi-asserted-by":"publisher","DOI":"10.1097\/00005537-200210000-00030"},{"key":"e_1_2_6_21_2","doi-asserted-by":"publisher","DOI":"10.1177\/000348941011900808"},{"key":"e_1_2_6_22_2","doi-asserted-by":"publisher","DOI":"10.1177\/000348940911800913"},{"key":"e_1_2_6_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.otohns.2009.08.022"},{"issue":"1","key":"e_1_2_6_24_2","first-page":"1","article-title":"Review article: reflux and its consequences\u2013the laryngeal, pulmonary and oesophageal manifestations. 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