Journal
JOURNAL OF ORAL PATHOLOGY & MEDICINE
Volume 44, Issue 10, Pages 801-809Publisher
WILEY
DOI: 10.1111/jop.12307
Keywords
4NQO; animal model; chemical carcinogenesis; Klf4; oral carcinogenesis
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Funding
- Argentinean National Research Council [PIP 2010-0302]
- National Agency for the Promotion of Science and Technology, Argentina [PICT 2011-1366]
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BackgroundSquamous cell carcinoma (SSC) of the head and neck is the sixth most common cancer and is rarely diagnosed in early stages. The transcription factor Kruppel-like factor 4 (Klf4) suppresses cell proliferation and promotes differentiation. Inducible mice carrying an oral-specific ablation of Klf4 (K14-CreER(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 (4NQO), a tobacco surrogate, to this conditional Klf4 knockout mice. MethodsK14-CreER(tam)/Klf4(flox/flox) and control mice were treated with 4NQO for 16weeks and monitored until week 30. Histopathological samples were used for diagnostic purposes and immunofluorescence detection of epithelial differentiation markers. Results4NQO-treated K14-CreER(tam)/Klf4(flox/flox) mice (Klf4KO 4NQO) showed a significant weight loss and developed more severe dysplastic lesions than control mice with 4NQO (P<0.005). The Klf4KO 4NQO 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 Klf4KO 4NQO mice exhibited reduced terminal differentiation as judged by cytokeratin 1 staining when compared with 4NQO-treated controls. ConclusionsKlf4 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 KLF4 as a tumor suppressor gene for the tongue epithelium.
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