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1.
J Virol ; 86(11): 6358-64, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22457518

RESUMEN

Infection with human papillomavirus type 16 (HPV-16) can lead to low- or high-grade squamous intraepithelial lesions (LSIL or HSIL). Here we show that these in vivo disease states can be replicated in raft cultures of early-pass HPV-16 episomal cell lines, at both the level of pathology and the level of viral gene expression. A reduced responsiveness to cell-cell contact inhibition and an increase in E6/E7 activity correlated closely with phenotype. Similar deregulation is likely to underlie the appearance of LSIL or HSIL soon after infection.


Asunto(s)
Carcinoma in Situ/virología , Inhibición de Contacto , Papillomavirus Humano 16/patogenicidad , Proteínas Oncogénicas Virales/metabolismo , Proteínas E7 de Papillomavirus/metabolismo , Proteínas Represoras/metabolismo , Neoplasias del Cuello Uterino/virología , Factores de Virulencia/metabolismo , Células Cultivadas , Femenino , Humanos , Técnicas In Vitro
2.
SLAS Discov ; 25(1): 79-86, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31361520

RESUMEN

Like cervical cancer, anal cancer is caused by human papillomavirus (HPV). HPV is the most common sexually transmitted agent and is found in the anal canal of almost all HIV-positive men who have sex with men (MSM). Rates of HPV anal cancer are disproportionately higher in this population. Although the nanovalent HPV vaccine is efficacious in protecting against oncogenic HPV types, a substantial proportion of MSM remains unvaccinated and anal HPV infection continues to be an important public health burden. Therefore, it is important to identify strategies to prevent HPV infection. We report on two promising and interlinked strategies: (1) the development of a cell-based Renilla luminescence reporter assay using HPV-16 pseudovirions that encapsidate SV40-driven Renilla luminescence reporter expression plasmid and (2) use of this assay for high-throughput screening (HTS) of FDA- and internationally approved drugs to identify those that could be repurposed to prevent HPV infection. We conducted a screen of 1906 drugs. The assay was valid with a Z' of 0.67 ± 0.04, percent coefficient of variance of 10.0, and signal-to-background noise window of 424.0 ± 8.0. Five drugs were chosen for further analyses based on selection parameters of ≥77.0% infection of HPV-16 pseudovirion-driven Renilla expression with <20.0% cytotoxicity. Of these, the antifungal pentamidine and a gamma-amino butyric acid receptor agonist securinine exhibited ≥90.0% infection with <10.0% cytotoxicity. This luminescent cell-based reporter expression plasmid assay for HTS is a valid method to identify FDA- and internationally approved drugs with the potential to be repurposed into prevention modalities for HPV infection.


Asunto(s)
Antivirales/farmacología , Evaluación Preclínica de Medicamentos , Genes Reporteros , Papillomavirus Humano 16/efectos de los fármacos , Proteínas Luminiscentes/genética , Plásmidos/genética , Línea Celular , Aprobación de Drogas , Ensayos Analíticos de Alto Rendimiento , Humanos , Reproducibilidad de los Resultados , Estados Unidos , United States Food and Drug Administration
3.
Clin Cancer Res ; 23(12): 3072-3083, 2017 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-27986750

RESUMEN

Purpose: Human papillomavirus (HPV) 16 plays an etiologic role in a growing subset of head and neck squamous cell carcinomas (HNSCC), where viral expression of the E6 and E7 oncoproteins is necessary for tumor growth and maintenance. Although patients with HPV+ tumors have a more favorable prognosis, there are currently no HPV-selective therapies. Recent studies identified differential receptor tyrosine kinase (RTK) profiles in HPV+ versus HPV- tumors. One such RTK, HER3, is overexpressed and interacts with phosphoinositide-3-kinase (PI3K) in HPV+ tumors. Therefore, we investigated the role of HPV oncoproteins in regulating HER3-mediated signaling and determined whether HER3 could be a molecular target in HPV+ HNSCC.Experimental Design: HER3 was investigated as a molecular target in HPV+ HNSCC using established cell lines, patient-derived xenografts (PDX), and human tumor specimens. A mechanistic link between HPV and HER3 was examined by augmenting E6 and E7 expression levels in HNSCC cell lines. The dependency of HPV+ and HPV- HNSCC models on HER3 was evaluated with anti-HER3 siRNAs and the clinical stage anti-HER3 monoclonal antibody KTN3379.Results: HER3 was overexpressed in HPV+ HNSCC, where it was associated with worse overall survival in patients with pharyngeal cancer. Further investigation indicated that E6 and E7 regulated HER3 protein expression and downstream PI3K pathway signaling. Targeting HER3 with siRNAs or KTN3379 significantly inhibited the growth of HPV+ cell lines and PDXs.Conclusions: This study uncovers a direct relationship between HPV infection and HER3 in HNSCC and provides a rationale for the clinical evaluation of targeted HER3 therapy for the treatment of HPV+ patients. Clin Cancer Res; 23(12); 3072-83. ©2016 AACR.


Asunto(s)
Carcinoma de Células Escamosas/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Terapia Molecular Dirigida , Infecciones por Papillomavirus/genética , Receptor ErbB-3/genética , Animales , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/virología , Línea Celular Tumoral , Elafina/genética , Regulación Neoplásica de la Expresión Génica/genética , Regulación Viral de la Expresión Génica/genética , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/patología , Neoplasias de Cabeza y Cuello/virología , Papillomavirus Humano 16/patogenicidad , Humanos , Ratones , Proteínas Oncogénicas Virales/genética , Proteínas E7 de Papillomavirus/genética , Infecciones por Papillomavirus/virología , ARN Interferente Pequeño/administración & dosificación , ARN Interferente Pequeño/genética , Receptor ErbB-3/antagonistas & inhibidores , Proteínas Represoras/genética , Carcinoma de Células Escamosas de Cabeza y Cuello , Ensayos Antitumor por Modelo de Xenoinjerto
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