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...
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2013
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oai:doaj.org-article:e32ca045d1634705983595653fa456a42021-11-18T08:55:31ZAnti-tumor activity of a miR-199-dependent oncolytic adenovirus.1932-620310.1371/journal.pone.0073964https://doaj.org/article/e32ca045d1634705983595653fa456a42013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24069256/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203The 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.Elisa CallegariBahaeldin K ElaminLucilla D'AbundoSimonetta FalzoniGiovanna DonvitoFarzaneh MoshiriMaddalena MilazzoGiuseppe AltavillaLuciano GiacomelliFrancesca FornariAkseli HemminkiFrancesco Di VirgilioLaura GramantieriMassimo NegriniSilvia SabbioniPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 9, p e73964 (2013) |
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Medicine R Science Q Elisa Callegari Bahaeldin K Elamin Lucilla D'Abundo Simonetta Falzoni Giovanna Donvito Farzaneh Moshiri Maddalena Milazzo Giuseppe Altavilla Luciano Giacomelli Francesca Fornari Akseli Hemminki Francesco Di Virgilio Laura Gramantieri Massimo Negrini Silvia Sabbioni Anti-tumor activity of a miR-199-dependent oncolytic adenovirus. |
| description |
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. |
| format |
article |
| author |
Elisa Callegari Bahaeldin K Elamin Lucilla D'Abundo Simonetta Falzoni Giovanna Donvito Farzaneh Moshiri Maddalena Milazzo Giuseppe Altavilla Luciano Giacomelli Francesca Fornari Akseli Hemminki Francesco Di Virgilio Laura Gramantieri Massimo Negrini Silvia Sabbioni |
| author_facet |
Elisa Callegari Bahaeldin K Elamin Lucilla D'Abundo Simonetta Falzoni Giovanna Donvito Farzaneh Moshiri Maddalena Milazzo Giuseppe Altavilla Luciano Giacomelli Francesca Fornari Akseli Hemminki Francesco Di Virgilio Laura Gramantieri Massimo Negrini Silvia Sabbioni |
| author_sort |
Elisa Callegari |
| title |
Anti-tumor activity of a miR-199-dependent oncolytic adenovirus. |
| title_short |
Anti-tumor activity of a miR-199-dependent oncolytic adenovirus. |
| title_full |
Anti-tumor activity of a miR-199-dependent oncolytic adenovirus. |
| title_fullStr |
Anti-tumor activity of a miR-199-dependent oncolytic adenovirus. |
| title_full_unstemmed |
Anti-tumor activity of a miR-199-dependent oncolytic adenovirus. |
| title_sort |
anti-tumor activity of a mir-199-dependent oncolytic adenovirus. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2013 |
| url |
https://doaj.org/article/e32ca045d1634705983595653fa456a4 |
| work_keys_str_mv |
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| _version_ |
1718421172971896832 |