Oral-specific ablation of Klf4 disrupts epithelial terminal

PAPARELLA M L; ABRIGO M.; BAL DE KIER JOFFé, E; ANA R RAIMONDI

JOURNAL OF ORAL PATHOLOGY AND MEDICINE

WILEY-BLACKWELL PUBLISHING, INC

Lugar: Londres; Año: 2015 vol. 44 p. 801 - 809

0904-2512

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 Krûppel-like factor 4 (Klf4) suppresses cell proliferation and promotes differentiation. Inducible mice carrying an oral-specific ablation of Klf4 (K14-CreERtam/Klf4flox/flox) develop mild dysplastic lesions and abnormal differentiation in the tongue. Aiming to analyze if Klf4 cooperate in oral chemical carcinogenesis we applied 4-nitroquinoline 1-oxide (4NQO), a tobacco surrogate, to this conditional Klf4 knockout mice. Methods: K14-CreERtam/Klf4flox/flox and control mice were treated with 4NQO in drinking water for 16 weeks and weekly monitored until week 30. Animals were euthanized for tissue collection. Histopathological samples were used for diagnostic purposes and immunofluorescence detection of epithelial differentiation markers. Results: 4NQO treated K14-CreERtam/Klf4flox/floxmice (KO 4NQO) showed a significant weight loss and developed more severe dysplastic lesions than control mice with 4NQO (p<0.005). The KO 4NQO showed a tendency to higher incidence of oral SCC and a marked keratinization pattern in dysplasias, in situ carcinomas and SCC. Also, KO 4NQO tongues exhibited fewer cytokeratin 1 labeled cells when compared with 4NQO 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. The results described here point Klf4 as a tumor suppressor gene for the tongue epithelium.