PAX9 regulates squamous cell differentiation and carcinogenesis in the oro‐oesophageal epithelium

• Published in: The Journal of pathology Vol. 244; no. 2; pp. 164 - 175
• Main Authors: Xiong, Zhaohui, Ren, Shuang, Chen, Hao, Liu, Yao, Huang, Caizhi, Zhang, Yawan Lyvia, Odera, Joab Otieno, Chen, Tong, Kist, Ralf, Peters, Heiko, Garman, Katherine, Sun, Zheng, Chen, Xiaoxin
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.02.2018; Wiley Subscription Services, Inc
• Subjects: Alcohol; Alcohol Drinking - adverse effects; Alcohols; Animals; Carcinogenesis; Cell Differentiation; Cell Line; Cell Proliferation; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cell Transformation, Neoplastic - pathology; Deoxyribonucleic acid; DNA; DNA Methylation; Drinking behavior; Epithelial cells; Epithelium; Esophageal Neoplasms - genetics; Esophageal Neoplasms - metabolism; Esophageal Neoplasms - pathology; Esophageal Squamous Cell Carcinoma - genetics; Esophageal Squamous Cell Carcinoma - metabolism; Esophageal Squamous Cell Carcinoma - pathology; Esophagus; Ethanol; Gene expression; Gene Expression Regulation, Neoplastic; Humans; Mice, Inbred C57BL; Mice, Knockout; N-Nitrosomethylbenzylamine; oesophagus; Paired Box Transcription Factors - deficiency; Paired Box Transcription Factors - genetics; Paired Box Transcription Factors - metabolism; PAX9; PAX9 Transcription Factor - genetics; PAX9 Transcription Factor - metabolism; promoter hypermethylation; Promoter Regions, Genetic; Risk Factors; Signal Transduction; Squamous cell carcinoma; Squamous Cell Carcinoma of Head and Neck - genetics; Squamous Cell Carcinoma of Head and Neck - metabolism; Squamous Cell Carcinoma of Head and Neck - pathology; Tongue; Tongue Neoplasms - genetics; Tongue Neoplasms - metabolism; Tongue Neoplasms - pathology; Transcriptome; ethanol; promoter hypermethylation; oesophagus; PAX9; squamous cell carcinoma
• ISSN: 0022-3417; 1096-9896; 1096-9896
• DOI: 10.1002/path.4998

PAX9 is a transcription factor of the PAX family characterized by a DNA‐binding paired domain. Previous studies have suggested a potential role of PAX9 in squamous cell differentiation and carcinogenesis of the oro‐oesophageal epithelium. However, its functional roles in differentiation and carcinogenesis remain unclear. In this study, Pax9 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 in vitro and mouse forestomach and tongue in vivo. We further showed that PAX9 was downregulated in human oro‐oesophageal squamous cell carcinoma (OESCC), and its downregulation was associated with alcohol drinking and promoter hypermethylation. Moreover, ad libitum feeding with a liquid diet containing ethanol for 40 weeks or Pax9 deficiency promoted N‐nitrosomethylbenzylamine‐induced squamous cell carcinogenesis in mouse tongue, oesophagus, and forestomach. In conclusion, PAX9 regulates squamous cell differentiation in the oro‐oesophageal epithelium. Alcohol drinking and promoter hypermethylation are associated with PAX9 silencing in human OESCC. PAX9 downregulation may contribute to alcohol‐associated oro‐oesophageal squamous cell carcinogenesis. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.