The interplay of UV and cutaneous papillomavirus infection in skin cancer development

Autores
Hasche, Daniel; Stephan, Sonja; Braspenning Wesch, Ilona; Mikulec, Julita; Niebler, Martina; Gröne, Hermann Josef; Flechtenmacher, Christa; Akgül, Baki; Rösl, Frank; Vinzon, Sabrina Eugenia
Año de publicación
2017
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Cutaneous human papillomaviruses (HPVs) are considered as cofactors for non-melanoma skin cancer (NMSC) development, especially in association with UVB. Extensively studied transgenic mouse models failed to mimic all aspects of virus-host interactions starting from primary infection to the appearance of a tumor. Using the natural model Mastomys coucha, which reflects the human situation in many aspects, we provide the first evidence that only UVB and Mastomys natalensis papillomavirus (MnPV) infection strongly promote NMSC formation. Using UVB exposures that correspond to UV indices of different geographical regions, irradiated animals developed either well-differentiated keratinizing squamous cell carcinomas (SCCs), still supporting productive infections with high viral loads and transcriptional activity, or poorly differentiated non-keratinizing SCCs almost lacking MnPV DNA and in turn, early and late viral transcription. Intriguingly, animals with the latter phenotype, however, still showed strong seropositivity, clearly verifying a preceding MnPV infection. Of note, the mere presence of MnPV could induce γH2AX foci, indicating that viral infection without prior UVB exposure can already perturb genome stability of the host cell. Moreover, as shown both under in vitro and in vivo conditions, MnPV E6/E7 expression also attenuates the excision repair of cyclobutane pyrimidine dimers upon UVB irradiation, suggesting a viral impact on the DNA damage response. While mutations of Ras family members (e.g. Hras, Kras, and Nras) were absent, the majority of SCCs harbored-like in humans-Trp53 mutations especially at two hot-spots in the DNA-binding domain, resulting in a loss of function that favored tumor dedifferentiation, counter-selective for viral maintenance. Such a constellation provides a reasonable explanation for making continuous viral presence dispensable during skin carcinogenesis as observed in patients with NMSC.
Fil: Hasche, Daniel. German Cancer Research Center; Alemania
Fil: Stephan, Sonja. German Cancer Research Center; Alemania
Fil: Braspenning Wesch, Ilona. German Cancer Research Center; Alemania
Fil: Mikulec, Julita. German Cancer Research Center; Alemania
Fil: Niebler, Martina. German Cancer Research Center; Alemania
Fil: Gröne, Hermann Josef. German Cancer Research Center; Alemania
Fil: Flechtenmacher, Christa. University Hospital Heidelberg;
Fil: Akgül, Baki. University of Cologne; Alemania
Fil: Rösl, Frank. German Cancer Research Center; Alemania
Fil: Vinzon, Sabrina Eugenia. German Cancer Research Center; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Materia
Papillomavirus
Mastomys coucha
Non-Melanoma Skin Cancer
UV
Dedifferentiation
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:11336/37405
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/37405
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling The interplay of UV and cutaneous papillomavirus infection in skin cancer developmentHasche, DanielStephan, SonjaBraspenning Wesch, IlonaMikulec, JulitaNiebler, MartinaGröne, Hermann JosefFlechtenmacher, ChristaAkgül, BakiRösl, FrankVinzon, Sabrina EugeniaPapillomavirusMastomys couchaNon-Melanoma Skin CancerUVDedifferentiationhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Cutaneous human papillomaviruses (HPVs) are considered as cofactors for non-melanoma skin cancer (NMSC) development, especially in association with UVB. Extensively studied transgenic mouse models failed to mimic all aspects of virus-host interactions starting from primary infection to the appearance of a tumor. Using the natural model Mastomys coucha, which reflects the human situation in many aspects, we provide the first evidence that only UVB and Mastomys natalensis papillomavirus (MnPV) infection strongly promote NMSC formation. Using UVB exposures that correspond to UV indices of different geographical regions, irradiated animals developed either well-differentiated keratinizing squamous cell carcinomas (SCCs), still supporting productive infections with high viral loads and transcriptional activity, or poorly differentiated non-keratinizing SCCs almost lacking MnPV DNA and in turn, early and late viral transcription. Intriguingly, animals with the latter phenotype, however, still showed strong seropositivity, clearly verifying a preceding MnPV infection. Of note, the mere presence of MnPV could induce γH2AX foci, indicating that viral infection without prior UVB exposure can already perturb genome stability of the host cell. Moreover, as shown both under in vitro and in vivo conditions, MnPV E6/E7 expression also attenuates the excision repair of cyclobutane pyrimidine dimers upon UVB irradiation, suggesting a viral impact on the DNA damage response. While mutations of Ras family members (e.g. Hras, Kras, and Nras) were absent, the majority of SCCs harbored-like in humans-Trp53 mutations especially at two hot-spots in the DNA-binding domain, resulting in a loss of function that favored tumor dedifferentiation, counter-selective for viral maintenance. Such a constellation provides a reasonable explanation for making continuous viral presence dispensable during skin carcinogenesis as observed in patients with NMSC.Fil: Hasche, Daniel. German Cancer Research Center; AlemaniaFil: Stephan, Sonja. German Cancer Research Center; AlemaniaFil: Braspenning Wesch, Ilona. German Cancer Research Center; AlemaniaFil: Mikulec, Julita. German Cancer Research Center; AlemaniaFil: Niebler, Martina. German Cancer Research Center; AlemaniaFil: Gröne, Hermann Josef. German Cancer Research Center; AlemaniaFil: Flechtenmacher, Christa. University Hospital Heidelberg;Fil: Akgül, Baki. University of Cologne; AlemaniaFil: Rösl, Frank. German Cancer Research Center; AlemaniaFil: Vinzon, Sabrina Eugenia. German Cancer Research Center; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaPublic Library Of Science2017-11info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/37405Hasche, Daniel; Stephan, Sonja; Braspenning Wesch, Ilona; Mikulec, Julita; Niebler, Martina; et al.; The interplay of UV and cutaneous papillomavirus infection in skin cancer development; Public Library Of Science; PLoS pathogens; 13; 11; 11-2017; 1-34; e10067231553-7374CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1006723info:eu-repo/semantics/altIdentifier/doi/10.1371/journal.ppat.1006723info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:40:08Zoai:ri.conicet.gov.ar:11336/37405instacron: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:34982025-09-29 09:40:08.407CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv The interplay of UV and cutaneous papillomavirus infection in skin cancer development
title The interplay of UV and cutaneous papillomavirus infection in skin cancer development
spellingShingle The interplay of UV and cutaneous papillomavirus infection in skin cancer development
Hasche, Daniel
Papillomavirus
Mastomys coucha
Non-Melanoma Skin Cancer
UV
Dedifferentiation
title_short The interplay of UV and cutaneous papillomavirus infection in skin cancer development
title_full The interplay of UV and cutaneous papillomavirus infection in skin cancer development
title_fullStr The interplay of UV and cutaneous papillomavirus infection in skin cancer development
title_full_unstemmed The interplay of UV and cutaneous papillomavirus infection in skin cancer development
title_sort The interplay of UV and cutaneous papillomavirus infection in skin cancer development
dc.creator.none.fl_str_mv Hasche, Daniel
Stephan, Sonja
Braspenning Wesch, Ilona
Mikulec, Julita
Niebler, Martina
Gröne, Hermann Josef
Flechtenmacher, Christa
Akgül, Baki
Rösl, Frank
Vinzon, Sabrina Eugenia
author Hasche, Daniel
author_facet Hasche, Daniel
Stephan, Sonja
Braspenning Wesch, Ilona
Mikulec, Julita
Niebler, Martina
Gröne, Hermann Josef
Flechtenmacher, Christa
Akgül, Baki
Rösl, Frank
Vinzon, Sabrina Eugenia
author_role author
author2 Stephan, Sonja
Braspenning Wesch, Ilona
Mikulec, Julita
Niebler, Martina
Gröne, Hermann Josef
Flechtenmacher, Christa
Akgül, Baki
Rösl, Frank
Vinzon, Sabrina Eugenia
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Papillomavirus
Mastomys coucha
Non-Melanoma Skin Cancer
UV
Dedifferentiation
topic Papillomavirus
Mastomys coucha
Non-Melanoma Skin Cancer
UV
Dedifferentiation
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Cutaneous human papillomaviruses (HPVs) are considered as cofactors for non-melanoma skin cancer (NMSC) development, especially in association with UVB. Extensively studied transgenic mouse models failed to mimic all aspects of virus-host interactions starting from primary infection to the appearance of a tumor. Using the natural model Mastomys coucha, which reflects the human situation in many aspects, we provide the first evidence that only UVB and Mastomys natalensis papillomavirus (MnPV) infection strongly promote NMSC formation. Using UVB exposures that correspond to UV indices of different geographical regions, irradiated animals developed either well-differentiated keratinizing squamous cell carcinomas (SCCs), still supporting productive infections with high viral loads and transcriptional activity, or poorly differentiated non-keratinizing SCCs almost lacking MnPV DNA and in turn, early and late viral transcription. Intriguingly, animals with the latter phenotype, however, still showed strong seropositivity, clearly verifying a preceding MnPV infection. Of note, the mere presence of MnPV could induce γH2AX foci, indicating that viral infection without prior UVB exposure can already perturb genome stability of the host cell. Moreover, as shown both under in vitro and in vivo conditions, MnPV E6/E7 expression also attenuates the excision repair of cyclobutane pyrimidine dimers upon UVB irradiation, suggesting a viral impact on the DNA damage response. While mutations of Ras family members (e.g. Hras, Kras, and Nras) were absent, the majority of SCCs harbored-like in humans-Trp53 mutations especially at two hot-spots in the DNA-binding domain, resulting in a loss of function that favored tumor dedifferentiation, counter-selective for viral maintenance. Such a constellation provides a reasonable explanation for making continuous viral presence dispensable during skin carcinogenesis as observed in patients with NMSC.
Fil: Hasche, Daniel. German Cancer Research Center; Alemania
Fil: Stephan, Sonja. German Cancer Research Center; Alemania
Fil: Braspenning Wesch, Ilona. German Cancer Research Center; Alemania
Fil: Mikulec, Julita. German Cancer Research Center; Alemania
Fil: Niebler, Martina. German Cancer Research Center; Alemania
Fil: Gröne, Hermann Josef. German Cancer Research Center; Alemania
Fil: Flechtenmacher, Christa. University Hospital Heidelberg;
Fil: Akgül, Baki. University of Cologne; Alemania
Fil: Rösl, Frank. German Cancer Research Center; Alemania
Fil: Vinzon, Sabrina Eugenia. German Cancer Research Center; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
description Cutaneous human papillomaviruses (HPVs) are considered as cofactors for non-melanoma skin cancer (NMSC) development, especially in association with UVB. Extensively studied transgenic mouse models failed to mimic all aspects of virus-host interactions starting from primary infection to the appearance of a tumor. Using the natural model Mastomys coucha, which reflects the human situation in many aspects, we provide the first evidence that only UVB and Mastomys natalensis papillomavirus (MnPV) infection strongly promote NMSC formation. Using UVB exposures that correspond to UV indices of different geographical regions, irradiated animals developed either well-differentiated keratinizing squamous cell carcinomas (SCCs), still supporting productive infections with high viral loads and transcriptional activity, or poorly differentiated non-keratinizing SCCs almost lacking MnPV DNA and in turn, early and late viral transcription. Intriguingly, animals with the latter phenotype, however, still showed strong seropositivity, clearly verifying a preceding MnPV infection. Of note, the mere presence of MnPV could induce γH2AX foci, indicating that viral infection without prior UVB exposure can already perturb genome stability of the host cell. Moreover, as shown both under in vitro and in vivo conditions, MnPV E6/E7 expression also attenuates the excision repair of cyclobutane pyrimidine dimers upon UVB irradiation, suggesting a viral impact on the DNA damage response. While mutations of Ras family members (e.g. Hras, Kras, and Nras) were absent, the majority of SCCs harbored-like in humans-Trp53 mutations especially at two hot-spots in the DNA-binding domain, resulting in a loss of function that favored tumor dedifferentiation, counter-selective for viral maintenance. Such a constellation provides a reasonable explanation for making continuous viral presence dispensable during skin carcinogenesis as observed in patients with NMSC.
publishDate 2017
dc.date.none.fl_str_mv 2017-11
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/11336/37405
Hasche, Daniel; Stephan, Sonja; Braspenning Wesch, Ilona; Mikulec, Julita; Niebler, Martina; et al.; The interplay of UV and cutaneous papillomavirus infection in skin cancer development; Public Library Of Science; PLoS pathogens; 13; 11; 11-2017; 1-34; e1006723
1553-7374
CONICET Digital
CONICET
url http://hdl.handle.net/11336/37405
identifier_str_mv Hasche, Daniel; Stephan, Sonja; Braspenning Wesch, Ilona; Mikulec, Julita; Niebler, Martina; et al.; The interplay of UV and cutaneous papillomavirus infection in skin cancer development; Public Library Of Science; PLoS pathogens; 13; 11; 11-2017; 1-34; e1006723
1553-7374
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1006723
info:eu-repo/semantics/altIdentifier/doi/10.1371/journal.ppat.1006723
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
dc.publisher.none.fl_str_mv Public Library Of Science
publisher.none.fl_str_mv Public Library Of Science
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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score 13.070432

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