title: Impairing squamous differentiation by Klf4 deletion is sufficient to initiate tongue carcinoma development upon K-Ras activation in mice.
abstract: Oral squamous cell carcinoma (SCC) is among the most prevalent cancers in the world and is characterized by high morbidity and few therapeutic options. Like most cancers, oral SCC arises from a multistep process involving alterations of genes responsible for balancing proliferation and differentiation. Among these, Krϋppel-like factor 4 (Klf4) suppresses cell proliferation and promotes differentiation and thus helps to maintain epithelial homeostasis. However, the prevailing role of Klf4 in maintenance of normal homeostasis in oral epithelium has not been established in vivo. Here, we used an inducible oral-specific mice model to selectively ablate Klf4 in the oral cavity. We generated K14-CreER(Tam)/Klf4 (f/f) mice that survived to adulthood and did not present overt phenotype. However, histologically these mice showed dysplastic lesions, increased cell proliferation and abnormal differentiation in the tongue 4 months after induction, supporting a homeostatic role of Klf4 in the oral epithelia. Furthermore, by breeding these mutants with a transgenic line expressing at endogenous levels K-ras (G12D), we assessed the role of disrupting differentiation gene programs to the carcinogenesis process. The K14-CreER(TAM)/K-ras (G12D)/Klf4 (-) (/-) mice rapidly develop oral SCC in the tongue. Thus, our findings support the emerging notion that activation of differentiating gene programs may represent a barrier preventing carcinogenesis in epithelial cells harboring oncogenic mutations, and thus that molecules acting upstream and downstream of Klf4 may represent components of a novel tumor-suppressive pathway.
authors.affiliation: Research Area, Institute of Oncology Angel H. Roffo, School of Medicine and.
authors.forename: Marianela
authors.initials: M
authors.lastname: Abrigo
authors.forename: Romina
authors.initials: R
authors.lastname: Alvarez
authors.forename: María L
authors.initials: ML
authors.lastname: Paparella
authors.forename: Diego E
authors.initials: DE
authors.lastname: Calb
authors.forename: Elisa
authors.initials: E
authors.lastname: Bal de Kier Joffe
authors.forename: J Silvio
authors.initials: JS
authors.lastname: Gutkind
authors.forename: Ana R
authors.initials: AR
authors.lastname: Raimondi
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics*; D017353:Gene Deletion; D018816:Genes, cdc; D011905:Genes, ras; D006706:Homeostasis; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics*; D051379:Mice; D010641:Phenotype; D014062:Tongue Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors