Shahrzad Shadabi1, Nargess Delrish2, Mehdi Norouzi2,3, Maryam Ehteshami1, Fariba Habibian-Sezavar4, Samira Pourrezaei2, Mobina Madihi2, Mohammadreza Ostadali5, Foruhar Akhgar4, Ali Shayeghpour1, Cobra Razavi Pashabayg2, Sepehr Aghajanian1, Sayed-Hamidreza Mozhgani6,7, Seyed-Mohammad Jazayeri8,9. 1. Student Research Committee, Alborz University of Medical Sciences, Karaj, Iran. 2. Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran. 3. Research Center for Clinical Virology, Tehran University of Medical Sciences, Tehran, Iran. 4. Blood Transfusion Research Center, High Institute for Research & Education in Transfusion Medicine, Tehran, Iran. 5. Hematology-Oncology and Stem Cell Transplantation Research Center, Shariati Hospital Tehran University of Medical Sciences, Tehran, Iran. 6. Non-communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran. hamidrezamozhgani@gmail.com. 7. Department of Microbiology, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran. hamidrezamozhgani@gmail.com. 8. Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran. jazayerism@sina.tums.ac.ir. 9. Research Center for Clinical Virology, Tehran University of Medical Sciences, Tehran, Iran. jazayerism@sina.tums.ac.ir.
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.
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 ATLLpatients. 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 ATLLpatients 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 humanATLL 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.