title: Oral-specific ablation of Klf4 disrupts epithelial terminal differentiation and increases premalignant lesions and carcinomas upon chemical carcinogenesis.
abstract: 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-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.
  
  
  METHODS
  K14-CreER(tam) /Klf4(flox/flox) and control mice were treated with 4NQO for 16 weeks and monitored until week 30. Histopathological samples were used for diagnostic purposes and immunofluorescence detection of epithelial differentiation markers.
  
  
  RESULTS
  4NQO-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.
  
  
  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 KLF4 as a tumor suppressor gene for the tongue epithelium.
authors.affiliation: Oral Pathology Department, School of Dentistry, University of Buenos Aires, Buenos Aires, Argentina.
authors.forename: María L
authors.initials: ML
authors.lastname: Paparella
authors.affiliation: Research Area, Institute of Oncology Angel H. Roffo, University of Buenos Aires, Buenos Aires, Argentina.
authors.forename: Marianela
authors.initials: M
authors.lastname: Abrigo
authors.affiliation: Research Area, Institute of Oncology Angel H. Roffo, University of Buenos Aires, Buenos Aires, Argentina.
authors.forename: Elisa
authors.initials: E
authors.lastname: Bal de Kier Joffe
authors.affiliation: Research Area, Institute of Oncology Angel H. Roffo, University of Buenos Aires, Buenos Aires, Argentina.
authors.forename: Ana R
authors.initials: AR
authors.lastname: Raimondi
mesh_terms: D015112:4-Nitroquinoline-1-oxide; D000818:Animals; D063646:Carcinogenesis / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D002273:Carcinogens; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation / Q000187:drug effects; D004195:Disease Models, Animal; D015870:Gene Expression; D006258:Head and Neck Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D007633:Keratins / Q000378:metabolism; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009061:Mouth Mucosa / Q000187:drug effects / Q000473:pathology; D009062:Mouth Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011230:Precancerous Conditions / Q000139:chemically induced / Q000473:pathology; D000077195:Squamous Cell Carcinoma of Head and Neck; D014062:Tongue Neoplasms / Q000139:chemically induced / Q000473:pathology
chemical_list: D002273:Carcinogens; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D015112:4-Nitroquinoline-1-oxide; D007633:Keratins
keywords: 4NQO; Klf4; animal model; chemical carcinogenesis; oral carcinogenesis