Oral‐specific ablation of Klf4 disrupts epithelial terminal differentiation and increases premalignant lesions and carcinomas upon chemical carcinogenesis

Background Squamous cell carcinoma ( SSC ) of the head and neck is the sixth most common cancer and is rarely diagnosed in early stages. The transcription factor Krϋppel‐like factor 4 ( Klf4 ) suppresses cell proliferation and promotes differentiation. Inducible mice carrying an oral‐specific ablation of Klf4 (K14‐Cre ER tam /Klf4 flox/flox ) develop mild dysplastic lesions and abnormal differentiation in the tongue. Aiming to analyze whether Klf4 cooperate in oral chemical carcinogenesis,we applied 4‐nitroquinoline 1‐oxide (4 NQO ), a tobacco surrogate, to this conditional Klf4 knockout mice. Methods K14‐Cre ER tam /Klf4 flox/flox and control mice were treated with 4 NQO for 16 weeks and monitored until week 30. Histopathological samples were used for diagnostic purposes and immunofluorescence detection of epithelial differentiation markers. Results 4 NQO ‐treated K14‐Cre ER tam /Klf4 flox/flox mice ( Klf4 KO 4 NQO ) showed a significant weight loss and developed more severe dysplastic lesions than control mice with 4 NQO ( P  < 0.005). The Klf4 KO 4 NQO showed a tendency to higher incidence of oral SCC and a marked keratinization pattern in dysplasias, in situ carcinomas and SCC . Also, tongues derived from Klf4 KO 4 NQO mice exhibited reduced terminal differentiation as judged by cytokeratin 1 staining when compared with 4 NQO ‐treated controls. Conclusions Klf4 ablation results in more severe dysplastic lesions in oral mucosa, with a tendency to higher incidence of SCC , after chemical carcinogenesis. We show here, in a context similar to the human carcinogenesis, that absence of Klf4 accelerates carcinogenesis and correlates with the absence of cytokeratin 1 expression. These results suggest a potential role for KLF 4 as a tumor suppressor gene for the tongue epithelium.