Laboratory of Cell Growth and Differentiation, Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan.
Department of Allergy and Immunology Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-cho, Iruma-gun, Saitama, 350-0495, Japan.
Sci Rep. 2017 Aug 10;7(1):7780. doi: 10.1038/s41598-017-07853-x.
Hepatitis B virus (HBV) infection is a leading cause of hepatocellular carcinoma worldwide. However, the strategy of HBV to escape from the host immune system remains largely unknown. In this study, we examined extracellular vesicles (EVs) secreted from human hepatocytes infected with HBV. EVs includeing exosomes are nano-size vesicles with proteins, mRNAs, and microRNAs (miRNAs), which can be transmitted to different cells. We found that 104 EV associated miRNAs were increased in hepatocytes more than 2-fold by HBV infection. We then selected those that were potentially implicated in immune regulation. Among them, five HBV-induced miRNAs were found to potentially target multiple sequences in the 3'UTR of IL-21, a cytokine that induces anti-viral immunity. Moreover, expression of a reporter gene with the 3' UTR of human IL-21 mRNA was suppressed by the five miRNAs individually. Finally, IL-21 expression in cloned human T cells was down-regulated by the five miRNAs. Collectively, this study identified the novel 3' UTR sequences of human IL-21 mRNA and potential binding sites of HBV-induced EV-miRNAs.
乙型肝炎病毒（HBV）感染是全球肝细胞癌的主要病因。然而，HBV 逃避宿主免疫系统的策略在很大程度上仍不清楚。在这项研究中，我们检测了感染 HBV 的人肝细胞分泌的细胞外囊泡（EVs）。EVs 包括外泌体，是具有蛋白质、mRNA 和 microRNAs（miRNAs）的纳米大小囊泡，可以传递到不同的细胞。我们发现，HBV 感染使肝细胞中 104 种与 EV 相关的 miRNAs 的表达增加了 2 倍以上。然后，我们选择了那些可能与免疫调节有关的 miRNA。其中，五种 HBV 诱导的 miRNA 被发现可能靶向 IL-21 3'UTR 中的多个序列，IL-21 是一种诱导抗病毒免疫的细胞因子。此外，报告基因与人类 IL-21 mRNA 的 3'UTR 的表达被五种 miRNA 分别抑制。最后，克隆的人类 T 细胞中的 IL-21 表达被这五种 miRNA 下调。总之，这项研究鉴定了人类 IL-21 mRNA 的新的 3'UTR 序列和 HBV 诱导的 EV-miRNA 的潜在结合位点。
