Regulation of hepatitis C virus by microRNA-122
ABSTRACT Most metazoan miRNAs (microRNAs) bind to sites in the 3'-UTRs (untranslated regions) of mRNA targets and negatively regulate protein synthesis. The liver-specific miR-122, however, exerts a positive effect on HCV (hepatitis C virus) RNA levels by binding directly to a site in the 5'-UTR of the viral RNA. HCV translation and RNA stability are unaffected, and therefore miR-122 is likely to act at the level of viral replication. The miR-122-binding site in HCV RNA was examined to determine whether the nature of the site is responsible for the unusual mode of action for a miRNA. When the site was placed in the 3'-UTR of a reporter mRNA, miR-122 repressed translation, and therefore the location of the miR-122-binding site dictates its effect on gene expression. Additionally, a second binding site for miR-122 was identified in the HCV 5'-UTR, and miR-122 binding to both sites in the same viral RNA was found to be necessary for viral replication. The two sites are adjacent and are separated by a short spacer, which is largely conserved between HCV genotypes. The binding site requirements for miR-122 to positively regulate HCV replication provide an insight into this unusual mode of miRNA action.
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ABSTRACT: tMicroRNAs (miRNAs) constitute an important class of non-coding RNA implicated in gene expression reg-ulation. More than 1900 miRNA molecules have been identified in humans and their modulation duringviral infection and it is recognized to play a role in latency regulation or in establishing an antiviral state.The liver cells are targets during DENV infection, and alteration of liver functions contributes to severedisease. In this work the miRNAs expression profile of the human hepatoma cell line, Huh-7, infected withDENV-2 was determined using microarray and real-time PCR. Let-7c is one of the miRNAs up-regulatedduring DENV infection in the hepatic Huh-7 as well as in the macrophage-monocytic cell line U937-DC-SIGN. Let-7c overexpression down-regulates both DENV-2 and DENV-4 infection. Additionally, we foundthat the transcription factor BACH1, a let-7c target, is also down-regulated during DENV infection. Inaccordance with this finding, HO-1, the main responsive factor of BACH1 was found up-regulated. Theup-regulation of HO-1 may contribute to the stress oxidative response in infected cellsVirus Research 01/2015; 196:105-112. DOI:10.1016/j.virusres.2014.11.010 · 2.83 Impact Factor
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ABSTRACT: Oligonucleotide-based therapies enable targeting and knockdown of targets that were previously considered un-druggable The development of oligonucleotide therapeutics targeting hepatocyte-expressed genes is progressing rapidly There is currently a large and growing pipeline of therapeutics, with the first systemic oligonucleotide therapy recently approved by the FDA.Journal of Hepatology 06/2013; DOI:10.1016/j.jhep.2013.05.045 · 10.40 Impact Factor
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ABSTRACT: Acute liver failure as life threatening condition comprises a difficult diagnostic situation to evaluate potential outcomes and therapeutic options. Thus, prognostic indicators are urgently needed for evaluation of progression of liver injury, clinical outcome, prognosis, and for therapeutic response. Recently, circulating microRNA, in particular miR-122, was described as a potential biomarker of acute liver injury after intoxication of mice. Circulating microRNA (miRNA) molecules are very stable and RNase-resistant due to protein aggregation and vesicle enclosure. Since miRNA species are known to be associated with chronic liver damage or with liver cancer, circulating miRNA patterns are suggested to serve also as reporters for progression of acute liver failure. miRNA profiling analyses using PCR arrays or next generation sequencing, may achieve identification of miRNA species that are linked to the rapid progression of acute liver injury, to the outcome of liver failure, or to the therapeutic response. Therefore, circulating miRNAs are promising, non-invasive biomarkers of future diagnostic approaches. However, normalisation of circulating miRNA levels is essential and further standardisation of miRNA quantification assays is needed.Frontiers in Physiology 12/2012; 3:476. DOI:10.3389/fphys.2012.00476