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. 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. 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. 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.

中文翻译：

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转录组数据集中差异表达微RNA的综合高通量荟萃分析揭示了成人T细胞白血病/淋巴瘤中MAPK/JNK信号转导通路的显着破坏

人类 T 淋巴细胞病毒 1 (HTLV-1) 感染可能导致成人 T 细胞白血病/淋巴瘤 (ATLL) 的发展。为了进一步阐明这种侵袭性 CD4+ T 细胞恶性肿瘤的病理生理学，我们采用了一种综合系统生物学方法来分析以前的转录组数据集，重点是 ATLL 患者外周血中差异表达的 miRNA (DEM)。数据集 GSE28626、GSE31629、GSE11577 用于识别 ATLL 特定的 DEM 签名。获取每个鉴定出的miRNA的靶基因，利用STRING数据库构建蛋白质-蛋白质相互作用网络。对目标基因中心进行进一步分析，以证明显着丰富的基因本体术语和信号通路。对通过网络分析确定的某些通路中的主要基因进行定量逆转录聚合酶链反应 (RTqPCR)，以突出基因表达的改变。高通量计算机分析显示 9 个 DEM hsa-let-7a、hsa-let-7g、hsa-mir-181b、hsa-mir-26b、hsa-mir-30c、hsa-mir-186、hsa-mir-10a 、 hsa-mir-30b 和 hsa-let-7f 在 ATLL 患者和健康供体之间。进一步分析显示，前 5 个 DEM 与先前确定的 HTLV-1 发病机制中的通路直接相关。网络分析表明目标基因中心参与了几个信号级联，主要是在 MAPK 通路中。对人 ATLL 样本的 RT-qPCR 显示，在 MAPK/JNK 通路中，EVI1、MKP1、PTPRR 和 JNK 基因与健康供体相比显着上调。结果强调了 ATLL 中失调的 microRNA 子集对细胞基因表达和信号转导途径的功能影响。需要进一步的研究来识别新的生物标志物，以获得 ATLL 中失调的生物途径的全面图谱。