Abstract
BackgroundHuman T-lymphotropic virus 1 (HTLV-1) infection may lead to the development of Adult T-cell leukemia/lymphoma (ATLL). To further elucidate the pathophysiology of this aggressive CD4+ T-cell malignancy, we have performed an integrated systems biology approach to analyze previous transcriptome datasets focusing on differentially expressed miRNAs (DEMs) in peripheral blood of ATLL patients.MethodsDatasets GSE28626, GSE31629, GSE11577 were used to identify ATLL-specific DEM signatures. The target genes of each identified miRNA were obtained to construct a protein-protein interactions network using STRING database. The target gene hubs were subjected to further analysis to demonstrate significantly enriched gene ontology terms and signaling pathways. Quantitative reverse transcription Polymerase Chain Reaction (RTqPCR) was performed on major genes in certain pathways identified by network analysis to highlight gene expression alterations.ResultsHigh-throughput in silico analysis revealed 9 DEMs hsa-let-7a, hsa-let-7g, hsa-mir-181b, hsa-mir-26b, hsa-mir-30c, hsa-mir-186, hsa-mir-10a, hsa-mir-30b, and hsa-let-7f between ATLL patients and healthy donors. Further analysis revealed the first 5 of DEMs were directly associated with previously identified pathways in the pathogenesis of HTLV-1. Network analysis demonstrated the involvement of target gene hubs in several signaling cascades, mainly in the MAPK pathway. RT-qPCR on human ATLL samples showed significant upregulation of EVI1, MKP1, PTPRR, and JNK gene vs healthy donors in MAPK/JNK pathway.DiscussionThe results highlighted the functional impact of a subset dysregulated microRNAs in ATLL on cellular gene expression and signal transduction pathways. Further studies are needed to identify novel biomarkers to obtain a comprehensive mapping of deregulated biological pathways in ATLL.
Highlights
Human T lymphotropic virus 1 (HTLV-1) is a singlestranded positive-strand RNA virus, which primarily infects CD4+ T-cells in humans [1]
Further analysis revealed the first 5 of differentially expressed miRNAs (DEMs) were directly associated with previously identified pathways in the pathogenesis of Human T-lymphotropic virus 1 (HTLV-1)
Network analysis demonstrated the involvement of target gene hubs in several signaling cascades, mainly in the MAPK pathway
Summary
Human T lymphotropic virus 1 (HTLV-1) is a singlestranded positive-strand RNA virus, which primarily infects CD4+ T-cells in humans [1]. A subpopulation of individuals infected with HTLV-1 (6% of male and of 2% female subjects) develop Adult T-cell leukemia/lymphoma (ATLL) after a long latency period of 4 to 6 decades [3, 4]. ATLL is a malignant T-cell neoplasm characterized by pleomorphic leukemic cells with hyper segmented nuclei, which are immunophenotypically comparable to regulatory T-cells [5]. This aggressive peripheral T-cell malignancy is associated with a poor prognosis and numerous clinical complications, such as hypercalcemia and immunodeficiency [4]. Human T-lymphotropic virus 1 (HTLV-1) infection may lead to the development of Adult T-cell leukemia/lymphoma (ATLL). To further elucidate the pathophysiology of this aggressive CD4+ T-cell malignancy, we have performed an integrated systems biology approach to analyze previous transcriptome datasets focusing on differentially expressed miRNAs (DEMs) in peripheral blood of ATLL patients
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