Department of Tumor Virology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
Adv Cancer Res. 2010;107:119-36. doi: 10.1016/S0065-230X(10)07004-1.
Epstein-Barr virus (EBV)-encoded small RNAs (EBERs) are noncoding RNAs that are expressed abundantly in latently EBV-infected cells. Previous studies demonstrated that EBERs (EBER1 and EBER2) play significant roles in various EBV-infected cancer cells. EBERs are responsible for malignant phenotypes of Burkitt's lymphoma (BL) cells including resistance to apoptosis. In addition, EBERs induce the expression of interleukin (IL)-10 in BL cells, insulin-like growth factor (IGF)-1 in gastric carcinoma and nasopharyngeal carcinoma cells, IL-9 in T cells that act as an autocrine growth factor. It was also reported that EBERs play critical roles in the B cell growth transformation including IL-6 induction by EBER2. EBERs have been discovered to interact with cellular proteins that play a key role in antiviral innate immunity. They bind the protein kinase RNA-dependent (PKR) and inhibit its activation, leading to resistance to PKR-mediated apoptosis. Recently, it was demonstrated that EBERs bind RIG-I and activate its downstream signaling, which induces expression of type-I interferon (IFN)s. Furthermore, EBERs induce IL-10 through IRF3 but not NF-kappaB activation in BL cells, suggesting that modulation of innate immune signaling by EBERs contribute to EBV-mediated oncogenesis. Most recently, it was reported that EBERs are secreted from EBV-infected cells and are recognized by toll-like receptor (TLR)3, leading to induction of type-I IFNs and inflammatory cytokines, and subsequent immune activation. Furthermore, EBER1 could be detected in the sera of patients with active EBV infectious diseases, suggesting that activation of TLR3 signaling by EBER1 would be account for the pathogenesis of active EBV infectious diseases.
EB 病毒编码的小 RNA（EBERs）是大量表达于潜伏性 EBV 感染细胞中的非编码 RNA。先前的研究表明，EBERs（EBER1 和 EBER2）在各种 EBV 感染的癌细胞中发挥重要作用。EBERs 负责伯基特淋巴瘤（BL）细胞的恶性表型，包括抗细胞凋亡。此外，EBERs 诱导 BL 细胞中白细胞介素（IL）-10 的表达、胃癌和鼻咽癌细胞中胰岛素样生长因子（IGF）-1 的表达、T 细胞中 IL-9 的表达，这些细胞因子作为自分泌生长因子发挥作用。据报道，EBERs 在 B 细胞生长转化中发挥关键作用，包括 EBER2 诱导 IL-6 的表达。已经发现 EBERs 与在抗病毒先天免疫中发挥关键作用的细胞蛋白相互作用。它们与蛋白激酶 RNA 依赖性（PKR）结合并抑制其激活，从而导致对 PKR 介导的细胞凋亡的抗性。最近，研究表明 EBERs 与 RIG-I 结合并激活其下游信号通路，诱导 I 型干扰素（IFN）的表达。此外，EBERs 通过 IRF3 而不是 NF-κB 激活诱导 BL 细胞中 IL-10 的表达，表明 EBERs 对先天免疫信号的调节有助于 EBV 介导的肿瘤发生。最近，有报道称，EBERs 从 EBV 感染的细胞中分泌出来，并被 Toll 样受体（TLR）3 识别，导致 I 型 IFNs 和炎症细胞因子的诱导，以及随后的免疫激活。此外，在患有活动性 EBV 传染病的患者血清中可以检测到 EBER1，表明 TLR3 信号的激活可能是导致活动性 EBV 传染病发病机制的原因。
