NOVEL ROLES OF MICRORNAS IN HEPATITIS C
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Abstract
Approximately, 170 million people are infected by hepatitis C virus (HCV) worldwide, and of these, nearly 85% will develop chronic hepatitis C (CHC). Despite finding new anti-viral treatment that increase response rate from 45 % to 65-70 %, investigations continue to find more effective treatments for hepatitis C because of side effects and limitations of current treatment. It is known that miR-122 enhances HCV replication by binding to two closely spaced target sites in the 5'-UTR of the viral genome, which leads to an increase in abundance of HCV RNA. We found that miR-122 down- regulates Occludin (OCLN), one of the key HCV receptors, by directly targeting 3'-UTR of OCLN mRNA. We also found that interaction of miR-122 with 3'-UTR of OCLN mRNA eventually results in a decrease in HCV entry. In accordance with our in vitro study, we found an inverse correlation between pre-treatment levels of miR-122 and HCV RNA levels in patients with CHC. This is a new finding of our study which is consonant with our hypothesis that miR-122 may play an antiviral role in uninfected hepatocytes and early stages of HCV infection. Protein Kinase R (PKR), a double-stranded RNA-dependent protein kinase, is among the well-known members of cellular antiviral proteins transcriptionally induced by IFNs in response to viral infection. We found that miR-122 down- regulates PRKRA expression by targeting 3'-UTR of PRKRA mRNA in uninfected Huh7.5 cells. This down-regulation led to decrease in phosphorylation of PKR. Our results are consonant with the notion that, in infected hepatocytes, miR-122 preferentially binds to 5'-UTR of HCV RNA rather than to the 3'-UTR of PRKRA, and this is the main factor that increases HCV replication. Based on our findings, both in vitro and in CHC patients, we speculate that miR-122 could play a dual role in HCV infection; in uninfected hepatocytes miR-122 plays an antiviral role through down-regulation of OCLN while, in infected hepatocytes, miR-122 increases HCV replication through binding to the 5'-UTR of HCV RNA. Our results suggest that miR-122 mimics may be more beneficial than miR-122 inhibitors in the earlier stages of infection or as a prophylactic approach when few or no hepatocytes are infected with HCV.Both responses to treatment as well as spontaneous outcome of HCV infection are critically affected by host genetic factors. We found that pre-treatment levels of hepatic miR-29b were significantly lower in CHC patients with early viral response (EVR) than those without EVR. This novel finding could be very important both for predicting the outcome of disease as well as suggesting new treatment approaches for chronic hepatitis C. Low levels of miR-29b in early responders to HCV therapy might potentially benefit future therapeutic interventions involving the use of miR-29 antagomirs. We also showed that miR-29b level serves as an independent factor for predicting advanced stages of fibrosis in patients with CHC. These findings are unexpected, because miR-29b has been shown to exhibit anti-fibrotic effects in vitro. Hence, caution should be exercised in extrapolating in vitro observations to subjects with CHC. Higher levels of mir-29b in these patients may suggest a role of over-expression of miR-29b as an anti-fibrotic factor in advanced degree of liver fibrosis as a healing process for liver. Broader translational and in vitro studies are needed to unravel the importance of miR-29b in prognosis and treatment of hepatitis C.