Cargando…

Anti-Tumor Activity of a miR-199-dependent Oncolytic Adenovirus

The down-regulation of miR-199 occurs in nearly all primary hepatocellular carcinomas (HCCs) and HCC cell lines in comparison with normal liver. We exploited this miR-199 differential expression to develop a conditionally replication-competent oncolytic adenovirus, Ad-199T, and achieve tumor-specifi...

Descripción completa

Detalles Bibliográficos
Autores principales: Callegari, Elisa, Elamin, Bahaeldin K., D’Abundo, Lucilla, Falzoni, Simonetta, Donvito, Giovanna, Moshiri, Farzaneh, Milazzo, Maddalena, Altavilla, Giuseppe, Giacomelli, Luciano, Fornari, Francesca, Hemminki, Akseli, Di Virgilio, Francesco, Gramantieri, Laura, Negrini, Massimo, Sabbioni, Silvia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3771938/
https://www.ncbi.nlm.nih.gov/pubmed/24069256
http://dx.doi.org/10.1371/journal.pone.0073964
Descripción
Sumario:The down-regulation of miR-199 occurs in nearly all primary hepatocellular carcinomas (HCCs) and HCC cell lines in comparison with normal liver. We exploited this miR-199 differential expression to develop a conditionally replication-competent oncolytic adenovirus, Ad-199T, and achieve tumor-specific viral expression and replication. To this aim, we introduced four copies of miR-199 target sites within the 3’ UTR of E1A gene, essential for viral replication. As consequence, E1A expression from Ad-199T virus was tightly regulated both at RNA and protein levels in HCC derived cell lines, and replication controlled by the level of miR-199 expression. Various approaches were used to asses in vivo properties of Ad-199T. Ad-199T replication was inhibited in normal, miR-199 positive, liver parenchyma, thus resulting in reduced hepatotoxicity. Conversely, the intrahepatic delivery of Ad-199T in newborn mice led to virus replication and fast removal of implanted HepG2 liver cancer cells. The ability of Ad-199T to control tumor growth was also shown in a subcutaneous xenograft model in nude mice and in HCCs arising in immune-competent mice. In summary, we developed a novel oncolytic adenovirus, Ad-199T, which could demonstrate a therapeutic potential against liver cancer without causing significant hepatotoxicity.