Comprehensive high-throughput meta-analysis of differentially expressed microRNAs in transcriptomic datasets reveals significant disruption of MAPK/JNK signal transduction pathway in Adult T-cell leukemia/lymphoma

Abstract

Background 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. Methods Datasets 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. Results High-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. Discussion The 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.

A Panel of Eight miRNAs Is Deregulated in HTLV-2 Infected PBMCs and BJABGu Cell Line

“…MiRNAs deregulated by HTLV-1 have been identified in recently published studies [ 5 , 28 , 35 , 36 , 37 , 38 , 39 ]. Interestingly, none of the eight miRNAs identified in our study were described to be deregulated in the presence of HTLV-1 or in subjects with ATL.…”

“…While MiRNA profiling has been extensively investigated in the context of HTLV-1 infection [ 5 , 28 , 35 , 36 , 37 , 38 , 39 ], evidence of HTLV-2’s impact on the miRNA expression is almost absent, except for only one study, which reported a profile of eight miRNAs common to both CD4+ T cells from HTLV-2 and HIV-1 mono-infected patients [ 40 ]. In the case of HTLV-1, alteration of the miRNA expression has been shown to be associated with the development of ATL and HAM/TSP disorders [ 5 ].…”

Potential miRNA-gene interactions determining progression of various ATLL cancer subtypes after infection by HTLV-1 oncovirus

“…The combination of chemotherapy drugs and miRNAs can be a suitable remedy for ATLL [9]. Several papers have introduced the genes and miRNAs implicated in the progression of ATLL without considering different subtypes [10][11][12]. Therefore, the exploration of miRNA-gene interactions in various ATLL subtypes to propose potential therapeutic targets using computational algorithms could be advantageous.…”