Kan Zunqi, Yan Wenli, Wang Ning, Fang Yuqing, Gao Huanyu, Song Yongmei
College of Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China.
Institute for Literature and Culture of Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China.
Front Genet. 2022 Jul 7;13:917454. doi: 10.3389/fgene.2022.917454. eCollection 2022.
Tetralogy of Fallot (TOF) is one of the most common cyanotic congenital heart diseases (CHD) worldwide; however, its pathogenesis remains unclear. Recent studies have shown that circular RNAs (circRNAs) act as "sponges" for microRNAs (miRNAs) to compete for endogenous RNA (ceRNA) and play important roles in regulating gene transcription and biological processes. However, the mechanism of ceRNA in TOF remains unclear. To explore the crucial regulatory connections and pathways of TOF, we obtained the human TOF gene, miRNA, and circRNA expression profiling datasets from the Gene Expression Omnibus (GEO) database. After data pretreatment, differentially expressed mRNAs (DEmRNAs), microRNAs (DEmiRNAs), and circRNAs (DEcircRNAs) were identified between the TOF and healthy groups, and a global triple ceRNA regulatory network, including circRNAs, miRNAs, and mRNAs based on the integrated data, was constructed. A functional enrichment analysis was performed on the Metascape website to explore the biological functions of the selected genes. Then, we constructed a protein-protein interaction (PPI) network and identified seven hub genes using the cytoHubba and MCODE plug-ins in the Cytoscape software, including BCL2L11, PIK3R1, SOCS3, OSMR, STAT3, RUNX3, and IL6R. Additionally, a circRNA-miRNA-hub gene subnetwork was established, and its enrichment analysis results indicated that the extrinsic apoptotic signaling pathway, JAK-STAT signaling pathway and PI3K-Akt signaling pathway may be involved in the pathogenesis of TOF. We further identified the hsa_circ_000601/hsa-miR-148a/BCL2L11 axis as a crucial signaling pathway axis from the subnetwork. This study provides a novel regulatory network for the pathogenesis of TOF, revealing the possible molecular mechanisms and crucial regulatory pathways that may provide new strategies for candidate diagnostic biomarkers or potential therapeutic targets for TOF.
法洛四联症（TOF）是全球最常见的青紫型先天性心脏病（CHD）之一；然而，其发病机制仍不清楚。最近的研究表明，环状RNA（circRNAs）作为微小RNA（miRNAs）的“海绵”来竞争内源性RNA（ceRNA），并在调节基因转录和生物学过程中发挥重要作用。然而，ceRNA在TOF中的机制仍不清楚。为了探索TOF的关键调控联系和途径，我们从基因表达综合数据库（GEO）中获取了人类TOF基因、miRNA和circRNA表达谱数据集。经过数据预处理后，在TOF组和健康组之间鉴定出差异表达的mRNA（DEmRNAs）、微小RNA（DEmiRNAs）和环状RNA（DEcircRNAs），并基于整合数据构建了一个包括circRNAs、miRNAs和mRNAs的全局三重ceRNA调控网络。在Metascape网站上进行了功能富集分析，以探索所选基因的生物学功能。然后，我们构建了一个蛋白质-蛋白质相互作用（PPI）网络，并使用Cytoscape软件中的cytoHubba和MCODE插件鉴定出七个枢纽基因，包括BCL2L11、PIK3R1、SOCS3、OSMR、STAT3、RUNX3和IL6R。此外，建立了一个circRNA-miRNA-枢纽基因子网，其富集分析结果表明，外源性凋亡信号通路、JAK-STAT信号通路和PI3K-Akt信号通路可能参与了TOF的发病机制。我们进一步从子网络中确定了hsa_circ_000601/hsa-miR-148a/BCL2L11轴作为关键信号通路轴。本研究为TOF的发病机制提供了一个新的调控网络，揭示了可能的分子机制和关键调控途径，可为TOF的候选诊断生物标志物或潜在治疗靶点提供新策略。
