INVESTIGADORES
RAIMONDI Ana Rosa
artículos
Título:
Impairing squamous differentiation by Klf4 deletion is sufficient to initiate tongue carcinoma development upon K-Ras activation in mice
Autor/es:
ABRIGO MARIANELA; ALVAREZ ROMINA; PAPARELLA MARIA L.; CALB DIEGO E; BAL DE KIER JOFFE; ELISA; GUTKIND SILVIO J.; RAIMONDI ANA R.
Revista:
CARCINOGENESIS
Editorial:
OXFORD UNIV PRESS
Referencias:
Lugar: Oxford; Año: 2014 vol. 35 p. 662 - 669
ISSN:
0143-3334
Resumen:
Impairing squamous differentiation by Klf4 deletion is sufficient to initiate tongue carcinoma development upon K-Ras activation in mice
Abrigo M, Alvarez R, Paparella M L, Calb D, Bal de Kier Joffe E, Gutkind J S and Raimondi A R.
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,
Krûppel-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-
CreERTam/Klf4f/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-rasG12D, we assessed the role of disrupting
differentiation gene programs to the carcinogenesis process. The
K14-CreERTAM/K-rasG12D/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.