Integration of Human and Viral miRNAs in Epstein-Barr Virus-Associated Tumors and Implications for Drug Repurposing

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.