Abstract 3785: Identification of potential cellular targets for Epstein-Barr virus encoded microRNAs miR-BART7 and miR-BART9 by in silico analysis

Abstract

Abstract The Epstein-Barr virus (EBV), formally designated human herpesvirus 4 (HHV-4), is an ubiquitous virus that causes lifelong latent infection in over 90% of the world's human adult population. EBV infection is regarded as carcinogenic to humans and associated with a variety of human cancers, especially endemic Burkitt lymphoma and nasopharyngeal carcinomas. EBV was the first human virus described to encode viral microRNAs (miRs), but the activity of EBV-encoded miRs in carcinogenesis remains to be fully elucidated. In this study we sought to identify novel potential targets for EBV-encoded miR-BART7 and miR-BART9 using in silicoanalysis. Mature sequences for EBV-miR-BARTs 7-3p, 7-5p, 9-3p, and 9-5p were retrieved from miRBase (http://www.mirbase.org, version 22) and 3’-UTRs from Homo sapiens were obtained from Ensembl (https://www.ensembl.org, version 92). RNAhybrid, miRanda, and PITA softwares were used for target predictions of miR-binding sites within 3’-UTRs of human mRNAs. Overlapped targets were collected using a custom Python script in such a way that only genes predicted by all the three algorithms were selected and used for gene-enrichment pathway analysis using the Cytoscape with the Reactome FI database plug-in (version 3.6.0). Each gene in a given pathway was counted as one hit using another custom Phyton script, and results were considered significant when P-value <0.05. As result, high-scoring predicted targets for EBV-miR-BARTs 7 and 9 were found to affect pathways involved in immune responses, gene expression, metabolism of proteins, and signal transduction. By targeting key tyrosine kinases pathways, such as epidermal growth factor receptor (EGFR), mitogen-activated protein kinase (MAPK), and vascular endothelial growth factor (VEGF), EBV-miR-BART7-3p was predicted to play a significant role in cell proliferation, cell cycle progression, and tumorigenesis. On the other hand, EBV- miR-BART7-5p was found to regulate adaptive immune system antigen presentation via MHC class II, cytokine signaling, and growth hormone receptor signaling. EBV-miR-BART9-3p was found as a relevant regulator for post-translational modification of proteins, WNT/β-catenin signaling, and pre-mRNA processing, while EBV-miR-BART9-5p could exert a role on signaling mediated by Rho GTPases, G protein- coupled receptors (GPCRs), gene silencing by small RNAs and RNA polymerase II transcription pathways. In conclusion, the results indicate pathways and genes that may be substantially targeted by EBV-miR- BARTs 7 and 9 and deserve further experimental investigation to disclose possible roles of EBV miRs on pathogenesis of cancers associated with viral infection. This work was supported by Sao Paulo Research Foundation (FAPESP) under grants 17/20352-0, 17/22312-5 and 17/23393-9. Citation Format: Brunno F. Caetano, Bárbara G. Müller-Coan, Rafael L. Coan, Bruno E. Fantinatti, Deilson E. de Oliveira. Identification of potential cellular targets for Epstein-Barr virus encoded microRNAs miR-BART7 and miR-BART9 by in silico analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3785.