Institute for Medical Immunology, Martin-Luther-University Halle-Wittenberg, Halle, Germany.
Institute for Pathology, Martin-Luther-University Halle-Wittenberg, Halle, Germany.
Oncoimmunology. 2023 Nov 27;12(1):2284483. doi: 10.1080/2162402X.2023.2284483. eCollection 2023.
The human Epstein-Barr virus (EBV), as a member of the human γ herpes viruses (HHV), is known to be linked with distinct tumor types. It is a double-stranded DNA virus and its genome encodes among others for 48 different microRNAs (miRs). Current research demonstrated a strong involvement of certain EBV-miRs in molecular immune evasion mechanisms of infected cells by, e.g., the disruption of human leukocyte antigen (HLA) class Ia and NKG2D functions. To determine novel targets of EBV-miRs involved in immune surveillance, ebv-miR-BART7-3p, an EBV-encoded miR with high expression levels during the different lytic and latent EBV life cycle phases, was overexpressed in human HEK293T cells. Using a cDNA microarray-based comparative analysis, 234 (229 downregulated and 5 upregulated) deregulated human transcripts were identified in ebv-miR-BART7-3p transfectants, which were mainly involved in cellular processes and molecular binding. A statistically significant downregulation of the anti-proliferative and tumor-suppressive hsa-miR-34A and the anti-viral interferon lambda (IFNL)3 mRNA was found. The ebv-miR-BART7-3p-mediated downregulation of IFNL3 expression was due to a direct interaction with the IFNL3 3'-untranslated region (UTR) as determined by luciferase reporter gene assays including the identification of the accurate ebv-miR-BART7-3p binding site. The effect of ebv-miR-BART7-3p on the IFNL3 expression was validated both in human cell lines and in human tissue specimen with known EBV status. These results expand the current knowledge of EBV-encoded miRs and their role in immune evasion, pathogenesis and malignant transformation.
人类 EB 病毒（EBV）作为人类γ疱疹病毒（HHV）的一员，已知与不同的肿瘤类型有关。它是一种双链 DNA 病毒，其基因组编码 48 种不同的 microRNAs（miRs）。目前的研究表明，某些 EBV-miRs 强烈参与受感染细胞的分子免疫逃逸机制，例如，破坏人类白细胞抗原（HLA）I 类和 NKG2D 功能。为了确定参与免疫监测的 EBV-miRs 的新靶标，在人类 HEK293T 细胞中过表达了 EBV 编码的 miR-BART7-3p，该 miR 在不同的裂解和潜伏 EBV 生命周期阶段具有高表达水平。使用基于 cDNA 微阵列的比较分析，在 ebv-miR-BART7-3p 转染细胞中鉴定出 234 个（229 个下调和 5 个上调）失调的人类转录本，它们主要参与细胞过程和分子结合。发现 ebv-miR-BART7-3p 转染的细胞中抗增殖和肿瘤抑制的 hsa-miR-34A 和抗病毒干扰素 lambda（IFNL）3 mRNA 的表达显著下调。ebv-miR-BART7-3p 介导的 IFNL3 表达下调是由于与 IFNL3 3'-非翻译区（UTR）的直接相互作用，通过荧光素酶报告基因测定包括鉴定 ebv-miR-BART7-3p 的准确结合位点来确定。ebv-miR-BART7-3p 对 IFNL3 表达的影响在具有已知 EBV 状态的人类细胞系和人类组织标本中得到了验证。这些结果扩展了 EBV 编码 miRs 及其在免疫逃逸、发病机制和恶性转化中的作用的现有知识。
