MicroRNAs are key post-transcriptional regulators of gene expression and their dysregulation is often linked to cancer. Epstein-Barr virus encodes 22 BamHI A Rightward Transcript (BART) miRNAs, which are expressed in nearly all EBV-associated cancers and implicated in viral pathogenesis. To investigate biological targets for BART miRNAs in B cell lymphomas, we performed a meta-analysis of publicly available Ago-CLIP datasets from EBV-positive Burkitt lymphomas (BLs), primary effusion lymphomas (PELs), AIDS-associated diffuse large B cell lymphomas (DLBCLs), and lymphoblastoid cell lines (LCLs). Our analysis focused on comparing targets of EBV BART miRNAs across the different types of transformed B cells. Using reporter assays, we then experimentally validated over 50 functional interactions between BART miRNAs and cellular protein-coding transcripts involved in activities such as B cell differentiation (PRDM1,IRF4, andMYC), cell cycle regulation (UHMK1, CDKN1A, MDM2, andNPAT), apoptosis (MCL1), signaling and intracellular trafficking (GAB1, SOS1, MAPK1, RAB11A, CAV1, andRANBP9), and tumor suppression (CCDC6). Moreover, ectopic BART miRNA expression in several EBV-negative BL cells induced transcriptional changes that may influence molecular signatures of EBV-associated BLs. Collectively, our findings reveal novel, functional interactions for BART miRNAs in lymphomas and provide insights into their roles in these B cell cancers.
微小核糖核酸（miRNAs）是基因表达的关键转录后调控因子，其功能失调常与癌症相关。爱泼斯坦-巴尔病毒编码22个BamHI A右向转录本（BART）miRNAs，这些分子在几乎所有EBV相关癌症中均有表达，并与病毒致病机制密切相关。为探究BART miRNAs在B细胞淋巴瘤中的生物学靶点，我们对公开的Ago-CLIP数据集进行了荟萃分析，数据来源于EBV阳性伯基特淋巴瘤（BLs）、原发性渗出性淋巴瘤（PELs）、艾滋病相关弥漫性大B细胞淋巴瘤（DLBCLs）以及淋巴母细胞样细胞系（LCLs）。本研究重点比较了不同类型转化B细胞中EBV BART miRNAs的靶标差异。通过报告基因检测实验，我们验证了50余组BART miRNAs与细胞蛋白编码转录本之间的功能性相互作用，这些靶基因涉及B细胞分化（PRDM1、IRF4和MYC）、细胞周期调控（UHMK1、CDKN1A、MDM2和NPAT）、细胞凋亡（MCL1）、信号传导与细胞内运输（GAB1、SOS1、MAPK1、RAB11A、CAV1和RANBP9）以及肿瘤抑制（CCDC6）等重要生物学过程。此外，在多个EBV阴性BL细胞中异位表达BART miRNAs可诱导转录水平变化，这可能影响EBV相关BLs的分子特征。综上所述，本研究揭示了BART miRNAs在淋巴瘤中新颖的功能性相互作用，为理解其在B细胞癌症中的作用机制提供了新见解。
Functional Targets for Epstein-Barr Virus BART MicroRNAs in B Cell Lymphomas
肿瘤(癌症)患者之家