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Previous studies have suggested a potential role of PAX9 in squamous cell differentiation and carcinogenesis of the oro\u2010oesophageal epithelium. However, its functional roles in differentiation and carcinogenesis remain unclear. In this study, <jats:italic>Pax9<\/jats:italic> deficiency in mouse oesophagus promoted cell proliferation, delayed cell differentiation, and altered the global gene expression profile. Ethanol exposure downregulated PAX9 expression in human oesophageal epithelial cells <jats:italic>in vitro<\/jats:italic> and mouse forestomach and tongue <jats:italic>in vivo<\/jats:italic>. We further showed that PAX9 was downregulated in human oro\u2010oesophageal squamous cell carcinoma (OESCC), and its downregulation was associated with alcohol drinking and promoter hypermethylation. Moreover, <jats:italic>ad libitum<\/jats:italic> feeding with a liquid diet containing ethanol for 40 weeks or <jats:italic>Pax9<\/jats:italic> deficiency promoted <jats:italic>N<\/jats:italic>\u2010nitrosomethylbenzylamine\u2010induced squamous cell carcinogenesis in mouse tongue, oesophagus, and forestomach. In conclusion, PAX9 regulates squamous cell differentiation in the oro\u2010oesophageal epithelium. Alcohol drinking and promoter hypermethylation are associated with PAX9 silencing in human OESCC. PAX9 downregulation may contribute to alcohol\u2010associated oro\u2010oesophageal squamous cell carcinogenesis. Copyright \u00a9 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/path.4998","type":"journal-article","created":{"date-parts":[[2017,10,21]],"date-time":"2017-10-21T04:42:35Z","timestamp":1508560955000},"page":"164-175","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["PAX9 regulates squamous cell differentiation and carcinogenesis in the oro\u2010oesophageal epithelium"],"prefix":"10.1002","volume":"244","author":[{"given":"Zhaohui","family":"Xiong","sequence":"first","affiliation":[{"name":"Department of Oral Medicine, Beijing Hospital for Stomatology Capital Medical University  Beijing PR China"},{"name":"Cancer Research Program, Julius L. 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