Faculty of Biological Science and Technology, Department of Cell and Molecular Biology and Microbiology, University of Isfahan, Isfahan, Iran.
Department of Microbiology, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran.
PLoS One. 2021 Feb 25;16(2):e0247713. doi: 10.1371/journal.pone.0247713. eCollection 2021.
Adult T-cell leukemia/lymphoma (ATLL) is virus-caused cancer that originates from the infection by human T-cell leukemia virus type 1. ATLL dysregulates various biological pathways related to the viral infection and cancer progression through the dysexpression of miRNAs and mRNAs. In this study, the potential regulatory subnetworks were constructed aiming to shed light on the pathogenesis mechanism of ATLL. For this purpose, two mRNA and one miRNA expression datasets were firstly downloaded from the GEO database. Next, the differentially expressed genes and miRNAs (DEGs and DE-miRNAs, respectively), as well as differentially co-expressed gene pairs (DCGs), were determined. Afterward, common DEGs and DCGs targeted by experimentally validated DE-miRNAs were explored. The oncogenic and anti-oncogenic miRNA-mRNA regulatory subnetworks were then generated. The expression levels of four genes and two miRNAs were examined in the blood samples by qRT-PCR. The members of three oncogenic/anti-oncogenic subnetworks were generally enriched in immune, virus, and cancer-related pathways. Among them, FZD6, THBS4, SIRT1, CPNE3, miR-142-3p, and miR-451a were further validated by real-time PCR. The significant up-regulation of FZD6, THBS4, and miR-451a as well as down-regulation of CPNE3, SIRT1, and miR-142-3p were found in ATLL samples than normal samples. The identified oncogenic/anti-oncogenic subnetworks are pieces of the pathogenesis puzzle of ATLL. The ultimate winner is probably an oncogenic network that determines the final fate of the disease. The identified genes and miRNAs are proposed as novel prognostic biomarkers for ATLL.
成人 T 细胞白血病/淋巴瘤（ATLL）是由人类 T 细胞白血病病毒 1 感染引起的病毒相关性癌症。ATLL 通过 miRNA 和 mRNA 的表达失调，扰乱了与病毒感染和癌症进展相关的各种生物学途径。在这项研究中，构建了潜在的调控子网络，旨在阐明 ATLL 的发病机制。为此，首先从 GEO 数据库中下载了两个 mRNA 和一个 miRNA 表达数据集。接下来，确定了差异表达基因和 miRNA（分别为 DEGs 和 DE-miRNAs）以及差异共表达基因对（DCGs）。然后，探索了实验验证的 DE-miRNA 靶向的共同 DEGs 和 DCGs。随后生成了致癌和抑癌 miRNA-mRNA 调控子网络。通过 qRT-PCR 在血液样本中检查了四个基因和两个 miRNA 的表达水平。三个致癌/抑癌子网络的成员通常富集在免疫、病毒和癌症相关途径中。其中，FZD6、THBS4、SIRT1、CPNE3、miR-142-3p 和 miR-451a 进一步通过实时 PCR 验证。在 ATLL 样本中发现 FZD6、THBS4 和 miR-451a 的显著上调以及 CPNE3、SIRT1 和 miR-142-3p 的下调。鉴定出的致癌/抑癌子网络是 ATLL 发病机制拼图的一部分。最终的胜利者可能是一个致癌网络，它决定了疾病的最终命运。鉴定出的基因和 miRNA 被提议作为 ATLL 的新型预后生物标志物。
