Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression primarily at the post-transcriptional level and play critical roles in a variety of physiological and pathological processes. In this report, miR-141 was identified to repress HBV expression by screening a small miRNA expressing library and synthetic miR-141 mimics could also significantly suppress HBV expression and replication in HepG2 cells. Bioinformatic analysis and experiment assays indicate that peroxisome proliferator-activated receptor alpha (PPARA) was the target of hsa-miR-141 during this process. Furthermore, knockdown of PPARA by small interfering RNA (siRNA) inhibited HBV replication similar to levels observed for miR-141. Promoter functional analysis indicated that repression of HBV replication by miR-141 mimics or siRNA was mediated by interfering with the HBV promoter functions, consistent with previous studies demonstrating that PPARA regulated HBV gene expression through interactions with HBV promoter regulatory elements. Our results suggest that miR-141 suppressed HBV replication by reducing HBV promoter activities by down-regulating PPARA. This study provides new insights into the molecular mechanisms associated with HBV-host interactions. Furthermore, this information may facilitate the development of novel anti-HBV therapeutic strategies.
Highlights
MicroRNAs are small noncoding RNAs with 18–25 nucleotides in length which are processed from short stem-loop precursors encoded by plant, animal and viral gemomes
HBV replication, 64 miRNAs functionally related to cell differentiation, viral infection and cancer were selected from a miRNA expression library. miRNA expression plasmids were cotransfected in triplicate into HepG2 cells with the pHBV1.3 plasmid
These analyses confirmed that miR141 could repress HBV replication effectively, and that miR-141 inhibitor transfection resulted in a pronounced increase in HBsAg/HBeAg expression had no significant effect on HBV DNA replication (Fig. 2)
Summary
MicroRNAs (miRNAs) are small noncoding RNAs with 18–25 nucleotides in length which are processed from short stem-loop precursors encoded by plant, animal and viral gemomes. MiRNAs have been shown to play significant roles in a variety of physiological processes including organ development, cell differentiation, apoptosis and metabolism by either mediating translational arrest or degrading target transcripts [4,5,6]. Jopling et al reported that miR-122 was necessary for hepatitis C virus (HCV) replication by binding of miRNAs to the 59 end of the viral genome [10]. We hypothesized whether hsa-miRNAs and HBV interactions could affect HBV replication. Among the candidate miRNAs, miR-141 was further analysized by considering its good inhibition rate of HBV replication. Results presented in this report demonstrated that miRNA-141 inhibited HBV replication by reducing the transcriptional ability of HBV promoters by targeting the transcription factor peroxisome proliferator-activated receptor alpha (PPARA)
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