Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, Taiwan, ROC.
Cell Mol Life Sci. 2012 Aug;69(15):2621-33. doi: 10.1007/s00018-012-0940-6. Epub 2012 Mar 6.
The non-coding microRNA (miRNA) is involved in the regulation of hepatitis C virus (HCV) infection and offers an alternative target for developing anti-HCV agent. In this study, we aim to identify novel cellular miRNAs that directly target the HCV genome with anti-HCV therapeutic potential. Bioinformatic analyses were performed to unveil liver-abundant miRNAs with predicted target sequences on HCV genome. Various cell-based systems confirmed that let-7b plays a negative role in HCV expression. In particular, let-7b suppressed HCV replicon activity and down-regulated HCV accumulation leading to reduced infectivity of HCVcc. Mutational analysis identified let-7b binding sites at the coding sequences of NS5B and 5'-UTR of HCV genome that were conserved among various HCV genotypes. We further demonstrated that the underlying mechanism for let-7b-mediated suppression of HCV RNA accumulation was not dependent on inhibition of HCV translation. Let-7b and IFNα-2a also elicited a synergistic inhibitory effect on HCV infection. Together, let-7b represents a novel cellular miRNA that targets the HCV genome and elicits anti-HCV activity. This study thereby sheds new insight into understanding the role of host miRNAs in HCV pathogenesis and to developing a potential anti-HCV therapeutic strategy.
非编码微小 RNA（miRNA）参与丙型肝炎病毒（HCV）感染的调控，为开发抗 HCV 药物提供了另一种靶标。本研究旨在鉴定具有抗 HCV 治疗潜力的直接靶向 HCV 基因组的新型细胞 miRNA。通过生物信息学分析揭示了在 HCV 基因组上具有预测靶序列的富含肝脏的 miRNA。各种基于细胞的系统证实 let-7b 在 HCV 表达中起负调控作用。特别是，let-7b 抑制 HCV 复制子活性并下调 HCV 积累，导致 HCVcc 的感染力降低。突变分析鉴定了 HCV 基因组编码序列和 5'-UTR 中 let-7b 的结合位点，这些结合位点在各种 HCV 基因型中是保守的。我们进一步证明，let-7b 介导的 HCV RNA 积累抑制的潜在机制不依赖于 HCV 翻译的抑制。let-7b 和 IFNα-2a 也对 HCV 感染产生协同抑制作用。总之，let-7b 代表一种新型的细胞 miRNA，可靶向 HCV 基因组并发挥抗 HCV 活性。本研究为理解宿主 miRNA 在 HCV 发病机制中的作用以及开发潜在的抗 HCV 治疗策略提供了新的见解。
