{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T07:32:01Z","timestamp":1777620721298,"version":"3.51.4"},"reference-count":60,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2020,4,25]],"date-time":"2020-04-25T00:00:00Z","timestamp":1587772800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Virginia Alden Wright","award":["Virginia Alden Wright"],"award-info":[{"award-number":["Virginia Alden Wright"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Cancers of the laryngopharynx represent the most devastating of the head and neck malignancies and additional risk factors are now epidemiologically linked to this disease. Using an in vivo model (Mus musculus C57Bl\/6J), we provide novel evidence that acidic bile (pH 3.0) progressively promotes invasive cancer in the hypopharynx. Malignant lesions are characterized by increasing: (i) oxidative DNA-damage, (ii) \u03b3H2AX expression, (iii) NF-\u03baB activation, and (iv) p53 expression. Histopathological changes observed in murine hypopharyngeal mucosa exposed to acidic bile were preceded by the overexpression of Tnf, Il6, Bcl2, Egfr, Rela, Stat3, and the deregulation of miR-21, miR-155, miR-192, miR-34a, miR-375, and miR-451a. This is the first study to document that acidic bile is carcinogenic in the upper aerodigestive tract. We showed that oxidative DNA-damage produced by acidic bile in combination with NF-\u03baB-related anti-apoptotic deregulation further supports the underlying two-hit hypothesized mechanism. Just as importantly, we reproduced the role of several biomarkers of progression that served as valuable indicators of early neoplasia in our experimental model. These findings provide a sound basis for proposing translational studies in humans by exposing new opportunities for early detection and prevention.<\/jats:p>","DOI":"10.3390\/cancers12051064","type":"journal-article","created":{"date-parts":[[2020,4,29]],"date-time":"2020-04-29T01:29:15Z","timestamp":1588123755000},"page":"1064","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["The Progressive Mutagenic Effects of Acidic Bile Refluxate in Hypopharyngeal Squamous Cell Carcinogenesis: New Insights"],"prefix":"10.3390","volume":"12","author":[{"given":"Clarence T.","family":"Sasaki","sequence":"first","affiliation":[{"name":"The Yale Larynx Laboratory, Department of Surgery, Yale School of Medicine, 310 Cedar Street (BML212), New Haven, CT 06510, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sotirios G.","family":"Doukas","sequence":"additional","affiliation":[{"name":"The Yale Larynx Laboratory, Department of Surgery, Yale School of Medicine, 310 Cedar Street (BML212), New Haven, CT 06510, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jose","family":"Costa","sequence":"additional","affiliation":[{"name":"Department of Pathology, Yale School of Medicine, New Haven, CT 06510, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9852-5790","authenticated-orcid":false,"given":"Dimitra P.","family":"Vageli","sequence":"additional","affiliation":[{"name":"The Yale Larynx Laboratory, Department of Surgery, Yale School of Medicine, 310 Cedar Street (BML212), New Haven, CT 06510, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,4,25]]},"reference":[{"key":"ref_1","unstructured":"American Cancer Society (2019, January 08). 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