Impairing squamous differentiation by Klf4 deletion is sufficient to initiate tongue carcinoma development upon K-Ras activation in mice

Autores
Abrigo, Marianela; Alvarez, Romina Soledad; Paparella, María Luisa; Calb, Diego E.; Bal, Elisa Dora; Gutkind, J. Silvio; Raimondi, Ana Rosa
Año de publicación
2013
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
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, Krupsilonppel-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/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-CreERTAM/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.
Fil: Abrigo, Marianela. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; Argentina
Fil: Alvarez, Romina Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; Argentina
Fil: Paparella, María Luisa. Universidad de Buenos Aires. Facultad de Odontología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Calb, Diego E.. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología; Argentina
Fil: Bal, Elisa Dora. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Gutkind, J. Silvio. National Institutes of Health; Estados Unidos
Fil: Raimondi, Ana Rosa. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Materia
Oral Cancer
Mutated Ras
Klf4
Transgenic Mice
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/29505
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/29505
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Impairing squamous differentiation by Klf4 deletion is sufficient to initiate tongue carcinoma development upon K-Ras activation in miceAbrigo, MarianelaAlvarez, Romina SoledadPaparella, María LuisaCalb, Diego E.Bal, Elisa DoraGutkind, J. SilvioRaimondi, Ana RosaOral CancerMutated RasKlf4Transgenic Micehttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Oral 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, Krupsilonppel-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/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-CreERTAM/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.Fil: Abrigo, Marianela. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; ArgentinaFil: Alvarez, Romina Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; ArgentinaFil: Paparella, María Luisa. Universidad de Buenos Aires. Facultad de Odontología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Calb, Diego E.. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología; ArgentinaFil: Bal, Elisa Dora. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Gutkind, J. Silvio. National Institutes of Health; Estados UnidosFil: Raimondi, Ana Rosa. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaOxford University Press2013-10info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/29505Abrigo, Marianela; Alvarez, Romina Soledad; Paparella, María Luisa; Calb, Diego E.; Bal, Elisa Dora; et al.; Impairing squamous differentiation by Klf4 deletion is sufficient to initiate tongue carcinoma development upon K-Ras activation in mice; Oxford University Press; Carcinogenesis; 35; 3; 10-2013; 662-6690143-3334enginfo:eu-repo/semantics/altIdentifier/doi/10.1093/carcin/bgt349info:eu-repo/semantics/altIdentifier/url/https://academic.oup.com/carcin/article/35/3/662/2463128info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-15T15:14:44Zoai:ri.conicet.gov.ar:11336/29505instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-15 15:14:44.662CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Impairing squamous differentiation by Klf4 deletion is sufficient to initiate tongue carcinoma development upon K-Ras activation in mice
title Impairing squamous differentiation by Klf4 deletion is sufficient to initiate tongue carcinoma development upon K-Ras activation in mice
spellingShingle Impairing squamous differentiation by Klf4 deletion is sufficient to initiate tongue carcinoma development upon K-Ras activation in mice
Abrigo, Marianela
Oral Cancer
Mutated Ras
Klf4
Transgenic Mice
title_short Impairing squamous differentiation by Klf4 deletion is sufficient to initiate tongue carcinoma development upon K-Ras activation in mice
title_full Impairing squamous differentiation by Klf4 deletion is sufficient to initiate tongue carcinoma development upon K-Ras activation in mice
title_fullStr Impairing squamous differentiation by Klf4 deletion is sufficient to initiate tongue carcinoma development upon K-Ras activation in mice
title_full_unstemmed Impairing squamous differentiation by Klf4 deletion is sufficient to initiate tongue carcinoma development upon K-Ras activation in mice
title_sort Impairing squamous differentiation by Klf4 deletion is sufficient to initiate tongue carcinoma development upon K-Ras activation in mice
dc.creator.none.fl_str_mv Abrigo, Marianela
Alvarez, Romina Soledad
Paparella, María Luisa
Calb, Diego E.
Bal, Elisa Dora
Gutkind, J. Silvio
Raimondi, Ana Rosa
author Abrigo, Marianela
author_facet Abrigo, Marianela
Alvarez, Romina Soledad
Paparella, María Luisa
Calb, Diego E.
Bal, Elisa Dora
Gutkind, J. Silvio
Raimondi, Ana Rosa
author_role author
author2 Alvarez, Romina Soledad
Paparella, María Luisa
Calb, Diego E.
Bal, Elisa Dora
Gutkind, J. Silvio
Raimondi, Ana Rosa
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv Oral Cancer
Mutated Ras
Klf4
Transgenic Mice
topic Oral Cancer
Mutated Ras
Klf4
Transgenic Mice
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv 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, Krupsilonppel-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/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-CreERTAM/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.
Fil: Abrigo, Marianela. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; Argentina
Fil: Alvarez, Romina Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; Argentina
Fil: Paparella, María Luisa. Universidad de Buenos Aires. Facultad de Odontología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Calb, Diego E.. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología; Argentina
Fil: Bal, Elisa Dora. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Gutkind, J. Silvio. National Institutes of Health; Estados Unidos
Fil: Raimondi, Ana Rosa. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
description 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, Krupsilonppel-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/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-CreERTAM/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.
publishDate 2013
dc.date.none.fl_str_mv 2013-10
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/29505
Abrigo, Marianela; Alvarez, Romina Soledad; Paparella, María Luisa; Calb, Diego E.; Bal, Elisa Dora; et al.; Impairing squamous differentiation by Klf4 deletion is sufficient to initiate tongue carcinoma development upon K-Ras activation in mice; Oxford University Press; Carcinogenesis; 35; 3; 10-2013; 662-669
0143-3334
url http://hdl.handle.net/11336/29505
identifier_str_mv Abrigo, Marianela; Alvarez, Romina Soledad; Paparella, María Luisa; Calb, Diego E.; Bal, Elisa Dora; et al.; Impairing squamous differentiation by Klf4 deletion is sufficient to initiate tongue carcinoma development upon K-Ras activation in mice; Oxford University Press; Carcinogenesis; 35; 3; 10-2013; 662-669
0143-3334
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1093/carcin/bgt349
info:eu-repo/semantics/altIdentifier/url/https://academic.oup.com/carcin/article/35/3/662/2463128
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Oxford University Press
publisher.none.fl_str_mv Oxford University Press
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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