{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T15:45:44Z","timestamp":1788363944325,"version":"build-2803163510"},"reference-count":51,"publisher":"Wiley","issue":"20","license":[{"start":{"date-parts":[[2019,7,16]],"date-time":"2019-07-16T00:00:00Z","timestamp":1563235200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Virginia Alden Wright Fund"}],"content-domain":{"domain":["acsjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer"],"published-print":{"date-parts":[[2019,10,15]]},"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Recent preclinical explorations strongly support the tumorigenic potential of bile on laryngopharyngeal mucosa. Herein, the authors describe, in bile\u2010related human hypopharyngeal squamous cell carcinoma (HSCC), NF\u2010<jats:italic>\u03ba<\/jats:italic>B\u2013related messenger RNA (mRNA) and microRNA (miRNA) oncogenic phenotypes similar to those previously identified in acidic bile\u2013exposed premalignant murine hypopharyngeal mucosa.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In this pilot study, the authors included human HSCC specimens paired with their adjacent normal tissue (ANT) derived from 3 representative patients with documented biliary laryngopharyngeal reflux (bile[+]) compared with 5 control patients without signs of bile reflux disease (bile[\u2010]). Immunohistochemical, quantitative polymerase chain reaction, and miRNA analyses were used to detect the levels of activated NF\u2010<jats:italic>\u03ba<\/jats:italic>B and expression levels of <jats:italic>STAT3, EGFR, BCL2, WNT5A, IL\u20106, IL\u20101B, \u0394Np63, cREL, TNF\u2010\u03b1<\/jats:italic>, <jats:italic>TP53, NOTCH1, NOTCH2, NOTCH3<\/jats:italic>, <jats:italic>miR\u201021, miR\u2010155, miR\u2010192, miR\u201034a<\/jats:italic>, <jats:italic>miR\u2010375, miR\u2010451a, miR\u2010489, miR\u2010504,<\/jats:italic> and <jats:italic>miR\u201099a<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Bile(+) HSCC demonstrated an intense NF\u2010<jats:italic>\u03ba<\/jats:italic>B activation accompanied by significant overexpression of <jats:italic>RELA(p65), EGFR, STAT3, BCL\u20102, cREL, \u0394Np63, WNT5A, IL\u20106<\/jats:italic>, and <jats:italic>IL1B<\/jats:italic>; upregulation of oncomir <jats:italic>miR\u201021<\/jats:italic>; and downregulation of tumor suppressor <jats:italic>miR\u2010375<\/jats:italic> compared with their respective ANTs. Bile(+) HSCC demonstrated significantly higher mRNA levels of all the analyzed genes, particularly <jats:italic>RELA(p65), IL\u20106, EGFR<\/jats:italic>, and <jats:italic>TNF\u2010\u03b1<\/jats:italic> compared with bile(\u2010) tumors. The <jats:italic>miR\u201021\/miR\u2010375<\/jats:italic> ratio, which previously has been linked to tumor aggressiveness, was found to be &gt;260\u2010fold and &gt;30\u2010fold higher, respectively, in bile(+) HSCCs compared with their ANTs and bile(\u2010) tumors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Although limitations apply to this pilot study due to the small number of patients with HSCC, the novel findings suggest that a history of bile as a component of esophageal reflux disease may represent an independent risk factor for hypopharyngeal carcinogenesis.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cncr.32369","type":"journal-article","created":{"date-parts":[[2019,7,16]],"date-time":"2019-07-16T09:44:20Z","timestamp":1563270260000},"page":"3554-3565","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":47,"title":["Biliary reflux as a causal factor in hypopharyngeal carcinoma: New clinical 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