inhibition in mice or primates does not result in any detectable liver toxicity. Role in cancer miR-122 levels are frequently reduced in hepatocellular carcinoma (HCC) compared to normal liver, and low miR-122 levels correlate with poor prognosis. Overexpression of miR-122 reduces tumorigenic properties in HCC cell lines, suggesting that it functions as a tumor suppressor gene, and increases the response of cells to the chemotherapeutic drugs sorafenib and doxorubicin. Several miR-122 target genes have been implicated in tumorigenesis, including ADAM10, IGF1R, CCNG1 and ADAM17. Innate Immunity Recent studies demonstrated that miR-122 may directly regulate different aspects of the interferons (IFNs) signaling pathway to enhanced induction of anti-viral genes and inhibition of various virus. Moreover, miR-122 have been shown to target various genes, resulting in enhancement of IFN signaling and subsequent antiviral innate immunity. Interferons (IFNs, includes type I and III interferon) treatment leads to a significant reduction in the expression of the liver-specific miR-122. HepG2 cells with overexpressed microRNA-122 mount an effective antiviral interferon response and innate immune response to hepatitis C virus (HCV), other RNA viruses and viral mimetics (e.g. poly(I:C)). Regulation of HCV Recent studies have shown that replication of hepatitis C virus (HCV) is dependent on miR-122 expression. miR-122 regulates HCV by binding directly to two adjacent sites close to the 5' end of HCV RNA. Although these experiments were conducted using genotype 1a and 1b HCV RNA, the miR-122 binding sites are highly conserved across different genotypes, and miR-122 is also required for replication of infectious type 2a HCV. As miRNAs generally function to repress gene expression by binding to 3'UTR sites, this positive regulation of viral replication via a 5'UTR represents a novel function for miR-122. The mechanism of regulation is not yet clear. miR-122 stimulates translation of HCV RNA, but not to a sufficient extent to explain its effects on viral replication, indicating that a second stage of the viral replication cycle must also be regulated. HCV RNA synthesis is not affected by miR-122, suggesting that regulation of other processes such as RNA stability may occur. The extent to which the miRNA-induced silencing complex (miRISC) is involved in this regulation has not been fully determined. The Argonaute proteins (Ago1–4), which are essential for miRNA-directed repression, appear to be necessary for miR-122 to regulate HCV, although miR-122 overexpression may overcome this requirement. The crystal structure of Ago2:miR-122 bound to the miR-122 binding site at the