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

Anti-Tumor Activity of a miR-199-dependent Oncolytic Adenovirus / Callegari E; Elamin BK; D'Abundo L; Falzoni S; Donvito G; Moshiri F; Milazzo M; Altavilla G; Giacomelli L; Fornari F; Hemminki A; Di Virgilio F; Gramantieri L; Negrini M; Sabbioni S. - In: PLOS ONE. - ISSN 1932-6203. - ELETTRONICO. - 8(9):e73964:(2013), pp. 1-16. [10.1371/journal.pone.0073964]

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

Fornari F;
2013

Abstract

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
2013
Anti-Tumor Activity of a miR-199-dependent Oncolytic Adenovirus / Callegari E; Elamin BK; D'Abundo L; Falzoni S; Donvito G; Moshiri F; Milazzo M; Altavilla G; Giacomelli L; Fornari F; Hemminki A; Di Virgilio F; Gramantieri L; Negrini M; Sabbioni S. - In: PLOS ONE. - ISSN 1932-6203. - ELETTRONICO. - 8(9):e73964:(2013), pp. 1-16. [10.1371/journal.pone.0073964]
Callegari E; Elamin BK; D'Abundo L; Falzoni S; Donvito G; Moshiri F; Milazzo M; Altavilla G; Giacomelli L; Fornari F; Hemminki A; Di Virgilio F; Gramantieri L; Negrini M; Sabbioni S
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/851022
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