Positive and negative modulation of viral and cellular mRNAs by liver-specific microRNA miR-122

microRNAs (miRNAs) are small RNAs that in general down-regulate the intracellular abundance and translation of target mRNAs. We noted that sequestration of liver-specific miR-122 by modified antisense oligonucleotides resulted in a dramatic loss of hepatitis C virus (HCV) RNA in Cultured human liver cells. A binding site for miR-122 was predicted to reside close to the 5' end of the viral genome, and its functionality was tested by Mutational analyses of the miRNA-binding site in viral RNA, resulting in reduced intracellular viral RNA abundance. Importantly, ectopic expression of miR-122 molecules that contained compensatory Mutations restored viral RNA abundance, revealing a genetic interaction between miR- 122 and the viral RNA genome. Studies with replication-defective vital RNAs demonstrated that miR-122 affected mRNA abundance by positively modulating RNA replication. In contrast, interaction of miR-122 with the 3'-noncoding region (3'NCR) of the cellular mRNA encoding the cationic amino acid transporter CAT-1 resulted in the down-regulation of CAT-1 protein abundance. These findings provide evidence that a specific miRNA call regulate distinct target mRNAs in both a positive and negative fashion. I he positive role of miR-122 in viral replication Suggests that this mRNA could be targeted for antiviral therapy.