The Second Clinical Medical College, Wenzhou Medical University, Wenzhou, PR China.
The First Clinical Medical College, Wenzhou Medical University, Wenzhou, PR China.
Life Sci. 2021 Jul 15;277:119455. doi: 10.1016/j.lfs.2021.119455. Epub 2021 Apr 5.
Pulmonary arterial hypertension (PAH) is a fatal cardiovascular disease with a cancer-like phenotype. Competing endogenous RNA (ceRNA) networks extensively involve in its pathological processes. But rare ceRNA networks and profound molecular mechanisms have been revealed in PAH. The aim of this study was to illuminate the ceRNA networks in PAH.
In this work, we have chosen the idiopathic PAH as an example. GSE15197 (mRNA) and GSE56914 (miRNA) from the Gene Expression Omnibus (GEO) were selected to explore key genes and novel ceRNA networks in PAH by a series of integrated bioinformatic analysis. To be more scientific, a part of pairs in identified ceRNA network were detected in hypoxia-induced HPASMCs. And the dual-luciferase assay was performed to certify the relationship between miRNAs and mRNAs.
Totally, 311 differentially expressed genes (DEGs) were identified and functional enrichment analysis illuminated that the majority of DEGs were enriched in proliferation, anti-apoptosis, inflammation and cancer-related pathways. And 10 hub genes were determined via Cytohubba after PPI network construction. Sequentially, with stepwise reverse prediction and pan-cancer co-expression analysis from mRNA to LncRNA in TargetScan, miRNet, ENCORI (Starbase V3.0) databases, a crucially ceRNA network was identified including 14 LncRNAs, 2 miRNAs, and 3 mRNAs. Further, in hypoxia-induced HPASMCs, the alterations of mRNAs, miRNAs and LncRNAs and their relationship were in accordance with the results we identified.
Consequently, the unique hub genes and ceRNA network we proposed may advance our understanding of the molecular mechanisms in PAH.
肺动脉高压（PAH）是一种致命的心血管疾病，具有类似癌症的表型。竞争内源性 RNA（ceRNA）网络广泛参与其病理过程。但在 PAH 中很少发现 ceRNA 网络和深刻的分子机制。本研究旨在阐明 PAH 中的 ceRNA 网络。
在这项工作中，我们选择特发性 PAH 作为一个例子。从基因表达综合数据库（GEO）中选择 GSE15197（mRNA）和 GSE56914（miRNA），通过一系列综合的生物信息学分析来探索 PAH 中的关键基因和新型 ceRNA 网络。为了更加科学，在缺氧诱导的 HPASMCs 中检测了鉴定的 ceRNA 网络中的一部分对。并进行双荧光素酶报告基因实验来验证 miRNA 和 mRNAs 之间的关系。
总共鉴定出 311 个差异表达基因（DEGs），功能富集分析表明，大多数 DEGs 富集在增殖、抗凋亡、炎症和癌症相关途径中。并且通过 PPI 网络构建后，Cytohubba 确定了 10 个枢纽基因。随后，通过从 mRNA 到 LncRNA 的逐步反向预测和泛癌共表达分析，在 TargetScan、miRNet、ENCORI（Starbase V3.0）数据库中，确定了一个关键的 ceRNA 网络，包括 14 个 LncRNAs、2 个 miRNAs 和 3 个 mRNAs。进一步，在缺氧诱导的 HPASMCs 中，mRNAs、miRNAs 和 LncRNAs 的变化及其关系与我们鉴定的结果一致。
因此，我们提出的独特的枢纽基因和 ceRNA 网络可能会促进我们对 PAH 中分子机制的理解。
