RT Journal Article
T1 A humanized mouse model of HPV-associated pathology driven by E7 expression
A1 Buitrago-Perez, Águeda
A1 Hachimi, Mariam
A1 Dueñas, Marta
A1 Lloveras, Belén
A1 Santos, Almudena
A1 Holguín, Almudena
A1 Duarte, Blanca
A1 Santiago, Juan Luis
A1 Akgül, Baki
A1 Rodríguez-Peralto, José L.
A1 Storey, Alan
A1 Rivas, Catalina
A1 Larcher Laguzzi, Fernando
A1 Río Nechaevsky, Marcela del
A1 Paramio, Jesús M.
A1 Garcia-Escudero, Ramón
AB Human 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.
PB Plos
SN 1932-6203
YR 2012
FD 2012-07-23
LK https://hdl.handle.net/10016/18882
UL https://hdl.handle.net/10016/18882
LA eng
NO This 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.
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RD 18 may. 2024