Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China.
Department of Hematology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, No. 16766, Jingshi Road, Lixia District, Jinan, Shandong, China.
Sci Rep. 2022 Mar 23;12(1):4973. doi: 10.1038/s41598-022-08930-6.
Cytogenetically normal acute myeloid leukemia (CN-AML) is a heterogeneous disease with different prognoses. Researches on prognostic biomarkers and therapy targets of CN-AML are still ongoing. Instead of protein-coding genes, more and more researches were focused on the non-coding RNAs especially long non-coding RNAs (lncRNAs) which may play an important role in the development of AML. Although a large number of lncRNAs have been found, our knowledge of their functions and pathological process is still in its infancy. The purpose of this research is to identify the key lncRNAs and explore their functions in CN-AML by reconstructing the lncRNA-miRNA-mRNA network based on the competitive endogenous RNA (ceRNA) theory. We reconstructed a global triple network based on the ceRNA theory using the data from National Center for Biotechnology Information Gene Expression Omnibus and published literature. According to the topological algorithm, we identified the key lncRNAs which had both the higher node degrees and the higher numbers of lncRNA-miRNA pairs and total pairs in the ceRNA network. Meanwhile, Gene Ontology (GO) and pathway analysis were performed using databases such as DAVID, KOBAS and Cytoscape plug-in ClueGO respectively. The lncRNA-miRNA-mRNA network was composed of 90 lncRNAs,33mRNAs,26 miRNAs and 259 edges in the lncRNA upregulated group, and 18 lncRNAs,11 mRNAs,6 miRNAs and 45 edges in the lncRNA downregulated group. The functional assay showed that 53 pathways and 108 GO terms were enriched. Three lncRNAs (XIST, TUG1, GABPB1-AS1) could possibly be selected as key lncRNAs which may play an important role in the development of CN-AML. Particularly, GABPB1-AS1 was highly expressed in CN-AML by both bioinformatic analysis and experimental verification in AML cell line (THP-1) with quantitative real-time polymerase chain reaction. In addition, GABPB1-AS1 was also negatively correlated with overall survival of AML patients. The lncRNA-miRNA-mRNA network revealed key lncRNAs and their functions in CN-AML. Particularly, lncRNA GABPB1-AS1 was firstly proposed in AML. We believe that GABPB1-AS1 is expected to become a candidate prognostic biomarker or a potential therapeutic target.
细胞遗传学正常的急性髓系白血病（CN-AML）是一种具有不同预后的异质性疾病。对 CN-AML 的预后生物标志物和治疗靶点的研究仍在进行中。除了蛋白质编码基因外，越来越多的研究集中在非编码 RNA 上，特别是长非编码 RNA（lncRNA），它们可能在 AML 的发展中发挥重要作用。尽管已经发现了大量的 lncRNA，但我们对它们的功能和病理过程的了解还处于起步阶段。本研究的目的是通过基于竞争性内源性 RNA（ceRNA）理论构建 lncRNA-miRNA-mRNA 网络，来鉴定关键的 lncRNA，并探讨它们在 CN-AML 中的功能。我们基于 ceRNA 理论，利用来自国家生物技术信息中心基因表达综合数据库和已发表文献的数据，构建了一个全局三重网络。根据拓扑算法，我们确定了关键的 lncRNA，这些 lncRNA 在 ceRNA 网络中具有较高的节点度和较高的 lncRNA-miRNA 对和总对数量。同时，分别使用 DAVID、KOBAS 和 Cytoscape 插件 ClueGO 等数据库进行基因本体论（GO）和通路分析。lncRNA 上调组的 lncRNA-miRNA-mRNA 网络由 90 个 lncRNA、33 个 mRNA、26 个 miRNA 和 259 个边缘组成，lncRNA 下调组由 18 个 lncRNA、11 个 mRNA、6 个 miRNA 和 45 个边缘组成。功能分析表明，有 53 条通路和 108 个 GO 术语被富集。三个 lncRNA（XIST、TUG1、GABPB1-AS1）可能被选为关键 lncRNA，它们可能在 CN-AML 的发展中发挥重要作用。特别是，通过生物信息学分析和 AML 细胞系（THP-1）的实时定量聚合酶链反应实验，发现 GABPB1-AS1 在 CN-AML 中高度表达。此外，GABPB1-AS1 与 AML 患者的总生存时间呈负相关。lncRNA-miRNA-mRNA 网络揭示了 CN-AML 中的关键 lncRNA 及其功能。特别是，lncRNA GABPB1-AS1 首先在 AML 中提出。我们相信，GABPB1-AS1 有望成为候选预后生物标志物或潜在治疗靶点。
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