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Hypopharyngeal cells (HCs) exposed to acidic bile present aberrant activation of STAT3, possibly contributing to its oncogenic effect. We hypothesized that STAT3 contributes substantially to the bile reflux\u2010induced molecular oncogenic profile, which can be suppressed by <jats:italic>STAT3<\/jats:italic> silencing or pharmacological inhibition. To explore our hypothesis, we targeted the STAT3 pathway, by knocking down <jats:italic>STAT3<\/jats:italic> (STAT3 siRNA), and inhibiting STAT3 phosphorylation (Nifuroxazide) or dimerization (SI3\u2010201; STA\u201021), in acidic bile (pH 4.0)\u2010exposed human HCs. Immunofluorescence, luciferase assay, Western blot, enzyme\u2010linked immunosorbent assay and qPCR analyses revealed that <jats:italic>STAT3<\/jats:italic> knockdown or pharmacologic inhibition significantly suppressed acidic bile\u2010induced STAT3 activation and its transcriptional activity, Bcl\u20102 overexpression, transcriptional activation of <jats:italic>IL6<\/jats:italic>, <jats:italic>TNF<\/jats:italic>\u2010<jats:italic>\u03b1<\/jats:italic>, <jats:italic>BCL2<\/jats:italic>, <jats:italic>EGFR<\/jats:italic>, <jats:italic>STAT3<\/jats:italic>, <jats:italic>RELA(p65)<\/jats:italic>, <jats:italic>REL<\/jats:italic> and <jats:italic>WNT5A<\/jats:italic>, and cell survival. Our novel findings document the important role of STAT3 in bile reflux\u2010related molecular oncogenic events, which can be dramatically prevented by <jats:italic>STAT3<\/jats:italic> silencing. STA\u201021, SI3\u2010201 or Nifuroxazide effectively inhibited STAT3 and cancer\u2010related inflammatory phenotype, encouraging their single or combined application in preventive or therapeutic strategies of bile reflux\u2010related hypopharyngeal carcinogenesis.<\/jats:p>","DOI":"10.1111\/jcmm.17011","type":"journal-article","created":{"date-parts":[[2021,12,1]],"date-time":"2021-12-01T08:51:56Z","timestamp":1638348716000},"page":"75-87","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Targeting STAT3 prevents bile reflux\u2010induced oncogenic molecular events linked to hypopharyngeal carcinogenesis"],"prefix":"10.1111","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9852-5790","authenticated-orcid":false,"given":"Dimitra P.","family":"Vageli","sequence":"first","affiliation":[{"name":"The Yale Larynx Laboratory Department of Surgery (Otolaryngology) Yale School of Medicine New Haven 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