Thakur Anamika, Kumar Manoj
Virology Unit and Bioinformatics Centre, Institute of Microbial Technology, Council of Scientific and Industrial Research (CSIR), Sector 39-A, Chandigarh, India.
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India.
OMICS. 2023 Mar;27(3):93-108. doi: 10.1089/omi.2023.0005.
Epstein-Barr virus (EBV) is associated with several tumors, and has substantial relevance for public health. Therapeutics innovation for EBV-related disorders is much needed. In this context, miRNAs are noncoding RNA molecules that play vital roles in EBV infection. miRNA-Seq and RNA-Seq data for EBV-associated clinical samples and cell lines have been generated, but their detailed integrative analyses, and exploitation for drug repurposing against EBV are lacking. Hence, we identified and analyzed the differentially expressed miRNAs (DEmiRs) in EBV-infected cell lines (28) and infected (28) and uninfected human tissue (20) samples using an in-house pipeline. We found significantly enriched host miRNAs like hsa-mir-3651, hsa-mir-1248, and hsa-mir-29c-3p in EBV-infected samples from EBV-associated nasopharyngeal carcinoma and Hodgkin's lymphoma, among others. Furthermore, we also identified significantly enriched novel miRNAs such as hsa-mir-29c-3p, hsa-mir-3651, and hsa-mir-98-3p, which were not previously reported in EBV-related tumors. Differentially expressed mRNAs (DEMs) were identified in EBV-infected cell lines (21) and uninfected human tissue (14) samples. We predicted and selected 1572 DEMs (upregulated) that are targeted by 547 DEmiRs (downregulated). These were further classified into essential (870) and nonessential (702) genes. Moreover, a miRNA-mRNA network was developed for the hub miRNAs. Importantly, we used the DEMs during EBV latent infection types I, II, and III to identify the candidate drugs for repurposing: Glyburide, Levodopa, Nateglinide, and Stiripentol, among others. To the best of our knowledge, this is the first integrative analyses that identified DEmiRs and DEMs as potential therapeutic targets and predicted drugs as potential candidates for repurposing against EBV-related tumors.
爱泼斯坦-巴尔病毒（EBV）与多种肿瘤相关，对公共卫生具有重要意义。迫切需要针对EBV相关疾病的治疗创新。在这种背景下，微小RNA（miRNA）是非编码RNA分子，在EBV感染中发挥着至关重要的作用。已经生成了EBV相关临床样本和细胞系的miRNA测序（miRNA-Seq）和RNA测序（RNA-Seq）数据，但缺乏对它们的详细综合分析以及用于EBV药物再利用的研究。因此，我们使用内部流程鉴定并分析了EBV感染的细胞系（28个）以及感染（28个）和未感染的人体组织（20个）样本中差异表达的miRNA（DEmiR）。我们发现在来自EBV相关鼻咽癌和霍奇金淋巴瘤等的EBV感染样本中，宿主miRNA如hsa-mir-3651、hsa-mir-1248和hsa-mir-29c-3p显著富集。此外，我们还鉴定出显著富集的新型miRNA，如hsa-mir-29c-3p、hsa-mir-3651和hsa-mir-98-3p，这些在之前的EBV相关肿瘤中未曾报道。在EBV感染的细胞系（21个）和未感染的人体组织（14个）样本中鉴定出差异表达的mRNA（DEM）。我们预测并选择了1572个被547个下调的DEmiR靶向的上调DEM。这些进一步被分类为必需基因（870个）和非必需基因（702个）。此外，还为核心miRNA构建了miRNA-mRNA网络。重要的是，我们利用I、II和III型EBV潜伏感染期间的DEM来鉴定用于再利用的候选药物：格列本脲、左旋多巴、那格列奈和司替戊醇等。据我们所知，这是首次进行的综合分析，将DEmiR和DEM鉴定为潜在治疗靶点，并预测药物为针对EBV相关肿瘤进行再利用的潜在候选药物。
