Oral cancer development upon Klf4 deletion and K-ras activation in a murine transgenic system

ABRIGO MARIANELA; ALVAREZ ROMINA; PAPARELLA M L; BAL DE KIER JOFFE, E; GUTKIND J.S.; RAIMONDI A. R.

Bariloche

Simposio; The Second South American Spring Symposium in Signal Transduction and Molecular Medicine.; 2012

Oral squamous cell carcinoma (OSCC) is among the most prevalent cancers in the world characterized by high morbidity, high mortality, and few therapeutic options outside of surgery, standard cytotoxic chemotherapy, and radiation. Like most cancer, OSCC is a disease that arises from a process that involves the sequential acquisition of genetic and epigenetic alterations in a variety of genes. Among these the TF Klf4 suppresses cell proliferation and promotes differentiation and thus helps to maintain homeostasis in epithelial cells of different organs. Here we analyze the function of Klf4 in oral keratinocytes homeostasis and its possible role in oral carcinogenesis upon K-ras activation. We took advantage of a transgenic mice model specific for oral cavity that we have previously developed (K14-CreERTam/K-rasG12D mice). Here, we generated a K14-CreERTam/Klf4 f/f mice and followed up progression of oral lesions. These animals survived to adulthood and did not present overt phenotype. However, histological examination showed that Klf4 ablation induced dysplastic lesions in the tongue by 6 months of age with increased basal cell proliferation (PCNA labeling index) and abnormal expression of cytokeratin 14. To asses Klf4 role in oral carcinogenesis we breed the K14-CreERTam/K-rasG12D mice with the Klf4f/f line. We found that K14-CreERTAM/K-rasG12D/ Klf4 -/- compound mice develop dysplastic lesions, in situ carcinomas and carcinomas, with a high incidence and latency as short as 3 weeks. The carcinomas did not express p21 and showed increased levels of CCDN1 and KLF5. Here, we provide evidence that Klf4 deletion and K-ras activation, when targeted specifically to the epithelium of the tongue, can trigger a series of events that are sufficient for full oral carcinogenesis.