MicroRNA silencing of tumor suppressor DLC-1 promotes efficient hepatitis C virus replication in primary human hepatocytes.
Hepatology
; 53(1): 53-61, 2011 Jan.
Article
em En
| MEDLINE
| ID: mdl-20967756
ABSTRACT
UNLABELLED MicroRNAs (miRNAs) are approximately 22-nucleotide noncoding RNAs that constitute silencers of target gene expression. Aberrant expression of miRNA has been linked to a variety of cancers, including hepatocellular carcinoma (HCC). Hepatitis C virus (HCV) infection is considered a major cause of chronic liver disease and HCC, although the mechanism of virus infection-associated hepatocarcinogenesis remains unclear. We report a direct role of miRNAs induced in HCV-infected primary human hepatocytes that target the tumor suppressor gene DLC-1 (a Rho GTPase-activating protein), which is frequently deleted in HCC, and other solid human tumors. MicroRNA miR-141 that targets DLC-1 was accentuated in cells infected with HCV genotypes 1a, 1b, and 2a. We present several lines of evidence that efficient HCV replication requires miR-141-mediated suppression of DLC-1. An increase in miR-141 correlated with the inhibition of DLC-1 protein in HCV-infected cells. Depletion of miR-141 with oligonucleotides complementary to the miRNAs inhibited virus replication, whereas artificially increased levels of intracellular miR-141 enhanced HCV replication. HCV-infected hepatocytes showed enhanced cell proliferation that can be countered by overexpression of DLC-1. CONCLUSION:
The collective results of this study suggest a novel mechanism of HCV infection-associated miRNA-mediated regulation of a tumor suppressor protein that has the ability to influence cell proliferation and HCV infection-mediated liver cancer.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Replicação Viral
/
Hepacivirus
/
Proteínas Ativadoras de GTPase
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Proteínas Supressoras de Tumor
/
MicroRNAs
Limite:
Humans
Idioma:
En
Revista:
Hepatology
Ano de publicação:
2011
Tipo de documento:
Article
País de afiliação:
Estados Unidos