Prediction of target genes for miR‐140‐5p in pulmonary arterial hypertension using bioinformatics methods

Abstract

The expression of micro RNA (miR)‐140‐5p is known to be reduced in both pulmonary arterial hypertension ( PAH ) patients and monocrotaline‐induced PAH models in rat. Identification of target genes for miR‐140‐5p with bioinformatics analysis may reveal new pathways and connections in PAH . This study aimed to explore downstream target genes and relevant signaling pathways regulated by miR‐140‐5p to provide theoretical evidences for further researches on role of miR‐140‐5p in PAH . Multiple downstream target genes and upstream transcription factors ( TF s) of miR‐140‐5p were predicted in the analysis. Gene ontology ( GO ) enrichment analysis indicated that downstream target genes of miR‐140‐5p were enriched in many biological processes, such as biological regulation, signal transduction, response to chemical stimulus, stem cell proliferation, cell surface receptor signaling pathways. Kyoto Encyclopedia of Genes and Genome ( KEGG ) pathway analysis found that downstream target genes were mainly located in Notch, TGF ‐beta, PI 3K/Akt, and Hippo signaling pathway. According to TF –mi RNA – mRNA network, the important downstream target genes of miR‐140‐5p were PPI , TGF ‐betaR1, smad4, JAG 1, ADAM 10, FGF 9, PDGFRA , VEGFA , LAMC 1, TLR 4, and CREB . After thoroughly reviewing published literature, we found that 23 target genes and seven signaling pathways were truly inhibited by miR‐140‐5p in various tissues or cells; most of these verified targets were in accordance with our present prediction. Other predicted targets still need further verification in vivo and in vitro .

miR-140 Attenuates the Progression of Early-Stage Osteoarthritis by Retarding Chondrocyte Senescence

“…40,41 A previous bioinformatics analysis revealed that the 3 0 UTRs of the key molecules in the Notch pathway, such as JAG1, ADAM10, and HEY1, possess miR-140 binding sites. 42 In our study, JAG1, NCSTN, KAT2B, and NUMBL were predicted as targets of miR-140 and were enriched in the Notch pathway, whereas ADAM10 and HEY1 were also predicted as targets of miR-140, although they were not enriched in the Notch pathway, according to the KEGG pathway analysis. This finding implies that one of the possible mechanisms by which miR-140 retards chondrocyte senescence is the regulation of the functions of the Notch pathway (Figure 6).…”

“…Downstream signaling molecules, such as HEY1 and HES1, mediate the catabolic effect of Notch signaling in chondrocytes, inducing the expression of many inflammatory cytokines and proteolytic enzymes, such as IL-1 receptor-like 1 (IL1RL1), MMP13, and ADAMTS5 40 , 41 . A previous bioinformatics analysis revealed that the 3′ UTRs of the key molecules in the Notch pathway, such as JAG1, ADAM10, and HEY1, possess miR-140 binding sites 42 . In our study, JAG1, NCSTN, KAT2B, and NUMBL were predicted as targets of miR-140 and were enriched in the Notch pathway, whereas ADAM10 and HEY1 were also predicted as targets of miR-140, although they were not enriched in the Notch pathway, according to the KEGG pathway analysis.…”

“…We found both in human and rat cartilage that the senescence-related markers, expressed mainly at the superficial layer of AC in E-OA and the related SnCC localization, might have important relevance for blocking cartilage regeneration, as cartilage progenitor cells (CPCs), a subtype of chondrocytes with potential stem cell properties, are mainly located in this region 48 , 49 . Notch and PI3K-AKT pathway-related molecules are expressed in both mesenchymal stem cells (MSCs) and CPCs, 39 , 42 , 43 and activation of the Notch pathway, especially by the JAG1-mediated route, significantly inhibits chondrogenic differentiation of MSCs by regulation of cellular senescence 42 , 50 , 51 . PI3K-AKT pathway activation can also promote MSC senescence 44 .…”

Long non-coding RNA PVT1 promotes proliferation and migration of pulmonary smooth muscle cells in pulmonary arterial hypertension through miR-140-5p/Fxr1 axis

“…As a multifunctional factor, miR-140-5p exerts essential roles in various pathological processes, such as osteogenesis [42], epithelial mesenchymal transition [43], and autophagy [44]. A comprehensive bioinformatics analysis also demonstrated that miR-140-5p was associated with 23 target genes and seven signaling pathways in multiple biological processes, such as signal transduction and cell proliferation [45]. The expression of miR-140-5p is downregulated in PAH and the suppression of miR-140-5p facilitates proliferation and migration in HPASMCs [46], which agrees with the observation in the present study.…”

M2 macrophages‐derived exosomal microRNA-501-3p promotes the progression of lung cancer via targeting WD repeat domain 82

“…Furthermore, miRNAs are known to bind the 3′-untranslated region of mRNA to degrade mRNA and therefore to negatively regulate relevant gene expression [ 34 ]. In this present study, we confirmed through bioinformatic prediction and dual luciferase reporter gene assay that there existed a targeting relationship between miR-501-3p and WDR82.…”