EBV-miR-BHRF1-2 targets PRDM1/Blimp1: potential role in EBV lymphomagenesis.
EBV-miR-BHRF1-2 targets PRDM1/Blimp1: potential role in EBV lymphomagenesis.
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作者：
Ma J;Nie K;Redmond D;Liu Y;Elemento O;Knowles DM;Tam W
PRDM1/Blimp1 是 B 细胞终末分化的主要调节因子，已被确定为侵袭性淋巴瘤（包括弥漫性大 B 细胞淋巴瘤 (DLBCL)）的抑癌基因。在 DLBCL 和霍奇金淋巴瘤中，PRDM1 被细胞 microRNA 下调。在这项研究中，我们确定了 Epstein-Barr 病毒 (EBV) microRNA (miRNA) EBV-miR-BHRF1-2 作为 PRDM1 的病毒 miRNA 调节因子。 EBV-miR-BHRF1-2 通过与 PRDM1 3' 非翻译区内的种子区域发生特异性相互作用来抑制荧光素酶报告基因活性。 EBV-miR-BHRF1-2 抑制上调类淋巴母细胞系 (LCL) 中的 PRDM1 蛋白表达，支持 miR-BHRF1-2 在体内 PRDM1 下调中的作用。 PRDM1 信使 RNA 和蛋白表达的不一致与 LCL 和原发性移植后 EBV 阳性 DLBCL 中的高 EBV-miR-BHRF1-2 水平相关。 LCL 细胞中 PRDM1 的强制表达诱导细胞凋亡和细胞周期停滞。抑制 EBV-miR-BHRF1-2 会负向调节细胞周期并降低 SCARNA20 的表达，SCARNA20 是一种小核仁 RNA，PRDM1 过表达也会下调。 EBV-miR-BHRF1-2与PRDM1之间的相互作用可能是EBV-miR-BHRF1-2促进EBV淋巴瘤发生的机制之一。我们的结果支持 EBV-miR-BHRF1-2 作为 EBV 相关淋巴瘤治疗靶点的潜力。
PRDM1/Blimp1, a master regulator of B-cell terminal differentiation, has been identified as a tumor suppressor gene in aggressive lymphomas, including diffuse large B-cell lymphoma (DLBCL). It has been shown in DLBCL and Hodgkin lymphoma that PRDM1 is downregulated by cellular microRNAs. In this study, we identify the Epstein–Barr virus (EBV) microRNA (miRNA), EBV-miR-BHRF1-2, as a viral miRNA regulator of PRDM1. EBV-miR-BHRF1-2 repressed luciferase reporter activity by specific interaction with the seed region within the PRDM1 3' untranslated region. EBV-miR-BHRF1-2 inhibition upregulated PRDM1 protein expression in lymphoblastoid cell lines (LCL), supporting a role of miR-BHRF1-2 in PRDM1 downregulation in vivo. Discordance of PRDM1 messenger RNA and protein expressions is associated with high EBV-miR-BHRF1-2 levels in LCLs and primary post-transplant EBV-positive DLBCL. Enforced expression of PRDM1-induced apoptosis and cell cycle arrest in LCL cells. Inhibition of EBV-miR-BHRF1-2 negatively regulates cell cycle and decreases expression of SCARNA20, a small nucleolar RNA that is also downregulated by PRDM1 overexpression. The interaction between EBV-miR-BHRF1-2 and PRDM1 may be one of the mechanisms by which EBV-miR-BHRF1-2 promotes EBV lymphomagenesis. Our results support the potential of EBV-miR-BHRF1-2 as a therapeutic target in EBV-associated lymphoma.