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A humanized mouse model of HPV-associated pathology driven by E7 expression

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dc.affiliation.dptoUC3M. Departamento de Bioingenieríaes
dc.affiliation.grupoinvUC3M. Grupo de Investigación: Tissue Engineering and Regenerative Medicine (TERMeG)es
dc.contributor.authorBuitrago-Perez, Águeda
dc.contributor.authorHachimi, Mariam
dc.contributor.authorDueñas, Marta
dc.contributor.authorLloveras, Belén
dc.contributor.authorSantos, Almudena
dc.contributor.authorHolguín, Almudena
dc.contributor.authorDuarte, Blanca
dc.contributor.authorSantiago, Juan Luis
dc.contributor.authorAkgül, Baki
dc.contributor.authorRodríguez-Peralto, José L.
dc.contributor.authorStorey, Alan
dc.contributor.authorRivas, Catalina
dc.contributor.authorLarcher Laguzzi, Fernando
dc.contributor.authorRío Nechaevsky, Marcela del
dc.contributor.authorParamio, Jesús M.
dc.contributor.authorGarcia-Escudero, Ramón
dc.date.accessioned2014-05-16T08:44:58Z
dc.date.available2014-05-16T08:44:58Z
dc.date.issued2012-07-23
dc.description.abstractHuman papillomavirus (HPV) is the causative agent of human cervical cancer and has been associated with oropharyngeal squamous cell carcinoma development. Although prophylactic vaccines have been developed, there is a need to develop new targeted therapies for individuals affected with malignant infected lesions in these locations, which must be tested in appropriate models. Cutaneous beta HPV types appear to be involved in skin carcinogenesis. Virus oncogenicity is partly achieved by inactivation of retinoblastoma protein family members by the viral E7 gene. Here we show that the E7 protein of cutaneous beta HPV5 binds pRb and promotes its degradation. In addition, we described an in vivo model of HPV-associated disease in which artificial human skin prepared using primary keratinocytes engineered to express the E7 protein is engrafted onto nude mice. Expression of E7 in the transplants was stably maintained for up to 6 months, inducing the appearance of lesions that, in the case of HPV16 E7, histologically resembled human anogenital lesions caused by oncogenic HPVs. Moreover, it was confirmed through biomarker expression analysis via immunodetection and/or quantitative PCR from mRNA and miRNA that the 16E7-modified engrafted skin shares molecular features with human HPV-associated pretumoral and tumoral lesions. Finally, our findings indicate a decrease of the in vitro capacity of HPV5 E7 to reduce pRb levels in vivo, possibly explaining the phenotypical differences when compared with 16E7-grafts. Our model seems to be a valuable platform for basic research into HPV oncogenesis and preclinical testing of HPV-associated antitumor therapies.es
dc.description.sponsorshipThis work was supported by Comunidad Autonoma de Madrid (Oncocycle S2006/BIO-0232), by Ministerio de Ciencia e Innovacion (ISCIII-RETIC RD06/0020 and SAF2008-00121), and by Fundación Sandra Ibarra. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.es
dc.format.extent19es
dc.format.mimetypeapplication/pdf
dc.identifier.bibliographicCitationA humanized mouse model of HPV-associated pathology driven by E7 expression. PLoS ONE, 7(7), e41743es
dc.identifier.doi10.1371/journal.pone.0041743
dc.identifier.issn1932-6203
dc.identifier.publicationfirstpage1
dc.identifier.publicationissue7, e41743
dc.identifier.publicationlastpage19
dc.identifier.publicationtitlePLoS ONE
dc.identifier.publicationvolume7
dc.identifier.urihttps://hdl.handle.net/10016/18882
dc.identifier.uxxiAR/0000012116
dc.language.isoeng
dc.publisherPlos
dc.relation.projectIDComunidad de Madrid. S2010/BMD-2420/CELLCAM
dc.relation.projectIDGobierno de España. SAF2008-00121
dc.relation.publisherversionhttp://dx.doi.org/10.1371/journal.pone.0041743
dc.rights© 2012 Buitrago-Perez et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en
dc.rights.accessRightsopen access
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/es/
dc.subject.ecienciaMedicinaes
dc.subject.otherCanceres
dc.subject.otherTherapeuticsen
dc.subject.otherClinical trialsen
dc.subject.otherWomen-Healthen
dc.subject.otherHuman-papillomavirus type-16en
dc.subject.otherCervical-carcinomaen
dc.titleA humanized mouse model of HPV-associated pathology driven by E7 expressionen
dc.typeresearch article*
dc.type.hasVersionVoR*
dspace.entity.typePublication
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