Construction of an oncolytic herpes simplex virus that precisely targets hepatocellular carcinoma cells.
Mol Ther
; 20(2): 339-46, 2012 Feb.
Article
em En
| MEDLINE
| ID: mdl-22146341
ABSTRACT
Selective replication in tumor cells is a highly desirable feature for oncolytic viruses. Recent studies have shown that microRNAs (miRNAs) play important roles in controlling gene expression, and that certain tissue-specific miRNAs are frequently downregulated in malignant cells. miR-122 is a liver-specific microRNA. It is abundantly expressed in normal hepatocytes but is absent in many hepatocellular carcinoma (HCC) cells. We hypothesized that expression of an essential viral gene by a liver-specific promoter would initially restrict virus replication to cells of hepatic origin and that adding miR-122 complementary sequences to the viral gene would make the transcripts degradable by miR-122 in normal hepatocytes, thus further confining its replication to HCC. We have constructed such an oncolytic herpes simplex virus by linking the essential viral glycoprotein H gene with the liver-specific apolipoprotein E (apoE)-AAT promoter and by adding the miR-122a complimentary sequence to the 3' untranslated region (3'UTR). To further increase the safety of this virus, complementary sequences from miR-124a and let-7 were also engineered into the same 3'UTR. Designated liver-cancer specific oncolytic virus (LCSOV), it was highly selective in killing HCC cells and in shrinking HCC xenografts. We conclude that LCSOV is a highly specific oncolytic virus that can precisely target HCC.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Simplexvirus
/
Carcinoma Hepatocelular
/
Vírus Oncolíticos
/
Tropismo Viral
/
Vetores Genéticos
/
Neoplasias Hepáticas
Limite:
Animals
/
Female
/
Humans
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article