Abstract:Background: MicroRNAsplayavitalroleincoronaryarterydisease.Abnormalex-pressionofmicroRNAshasbeenfoundtobeassociatedwiththeoccurrenceofCAD. Methods: WeidentifiedsignificantlydifferentiallyexpressedmicroRNAsinplasma between40patientswithCADand10controlswithNCAusingRNAsequencing.The differentiallyexpressedmicroRNAswereanalyzedforGeneOntology(GO)enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. Results: Fifty cDNA libraries were constructed and sequenced, and a total of 1871.82Mrawr… Show more
“…As important gene regulators, the miR-15b family is involved in the cell cycle, cellular proliferation and apoptosis, and has been found to be dysfunctional in various diseases [38]. Expression levels of miR-15b-3p have been reported to be significantly upregulated in rs363050 SNAP-25 GG homozygous Alzheimer's disease [39], Microcystin-LR-induced hepatotoxicity [40], myocardial ischemic reperfusion injury [41], coronary artery disease [42], and poor prognosis of hepatocellular carcinoma patients after curative hepatectomy [43]. Therefore, miR-15b-3p expression may be positively correlated with the progression of the disease.…”
Background: Exosomes are essential for tumor growth, metastasis, and are used as novel signaling molecules in targeted therapies. Therefore, exosomal miRNAs can be used in new diagnostic and therapeutic approaches due to their involvement in the development of cancers. However, the detailed biological function, potential molecular mechanism and clinical application of exo-miR-15b-3p in gastric cancer (GC) remains unclear.Methods: miR-15b-3p mRNA levels in tissues, serum, cells and exosomes were analyzed using qRT-PCR assays. qRT-PCR, immunohistochemical and western blotting analyses were utilized for the determination of DYNLT1 expression. The interrelationship connecting miR-15b-3p with DYNLT1 was verified using Dual-luciferase report, western blotting and qRT-PCR assays. Fluorescent PKH-26 or GFP-Lv-CD63 labeled exosomes, as well as Cy3-miR-15b-3p, were utilized to determine the efficacy of the transfer of exo-miR-15b-3p between BGC-823 and recipient cells. Several in vitro assays and xenograft tumor models were conducted to determine exo-miR-15b-3p impact on GC progression.Results: This is the first study to confirm high miR-15b-3p expression in GC cell lines, tissues and serum. Exosomes obtained from 108 GC patient serum samples and GC cell-conditioned medium were found to show upregulation of exo-miR-15b-3p, with the area under the ROC curve (AUC) being 0.820 [0.763-0.876], which is superior to the AUC of tissues and serum miR-15b-3p (0.674 [0.600-0.748] and 0.642 [0.499-0.786], respectively). In addition, high exo-miR-15b-3p expression in serum was found to accurately predict worse overall survival. SGC-7901 and GES-1 cells are capable of internalizing BGC-823 cell-derived exosomes, allowing the transfer of miR-15b-3p. Migration, invasion, proliferation and inhibition of apoptosis in vitro and in vivo were enhanced by exo-miR-15b-3p, by restraining DYNLT1, Cleaved Caspase-9 and Caspase-3 expression.Conclusions: This study identified a previously unknown regulatory pathway, exo-miR-15b-3p/DYNLT1/Caspase-3/ Caspase-9, which promotes GC development and GES-1 cell malignant transformation. Therefore, serum exo-miR-15b-3p may be a potential GC diagnosis and prognosis biomarker, which can be used in precise targeted GC therapy.
“…As important gene regulators, the miR-15b family is involved in the cell cycle, cellular proliferation and apoptosis, and has been found to be dysfunctional in various diseases [38]. Expression levels of miR-15b-3p have been reported to be significantly upregulated in rs363050 SNAP-25 GG homozygous Alzheimer's disease [39], Microcystin-LR-induced hepatotoxicity [40], myocardial ischemic reperfusion injury [41], coronary artery disease [42], and poor prognosis of hepatocellular carcinoma patients after curative hepatectomy [43]. Therefore, miR-15b-3p expression may be positively correlated with the progression of the disease.…”
Background: Exosomes are essential for tumor growth, metastasis, and are used as novel signaling molecules in targeted therapies. Therefore, exosomal miRNAs can be used in new diagnostic and therapeutic approaches due to their involvement in the development of cancers. However, the detailed biological function, potential molecular mechanism and clinical application of exo-miR-15b-3p in gastric cancer (GC) remains unclear.Methods: miR-15b-3p mRNA levels in tissues, serum, cells and exosomes were analyzed using qRT-PCR assays. qRT-PCR, immunohistochemical and western blotting analyses were utilized for the determination of DYNLT1 expression. The interrelationship connecting miR-15b-3p with DYNLT1 was verified using Dual-luciferase report, western blotting and qRT-PCR assays. Fluorescent PKH-26 or GFP-Lv-CD63 labeled exosomes, as well as Cy3-miR-15b-3p, were utilized to determine the efficacy of the transfer of exo-miR-15b-3p between BGC-823 and recipient cells. Several in vitro assays and xenograft tumor models were conducted to determine exo-miR-15b-3p impact on GC progression.Results: This is the first study to confirm high miR-15b-3p expression in GC cell lines, tissues and serum. Exosomes obtained from 108 GC patient serum samples and GC cell-conditioned medium were found to show upregulation of exo-miR-15b-3p, with the area under the ROC curve (AUC) being 0.820 [0.763-0.876], which is superior to the AUC of tissues and serum miR-15b-3p (0.674 [0.600-0.748] and 0.642 [0.499-0.786], respectively). In addition, high exo-miR-15b-3p expression in serum was found to accurately predict worse overall survival. SGC-7901 and GES-1 cells are capable of internalizing BGC-823 cell-derived exosomes, allowing the transfer of miR-15b-3p. Migration, invasion, proliferation and inhibition of apoptosis in vitro and in vivo were enhanced by exo-miR-15b-3p, by restraining DYNLT1, Cleaved Caspase-9 and Caspase-3 expression.Conclusions: This study identified a previously unknown regulatory pathway, exo-miR-15b-3p/DYNLT1/Caspase-3/ Caspase-9, which promotes GC development and GES-1 cell malignant transformation. Therefore, serum exo-miR-15b-3p may be a potential GC diagnosis and prognosis biomarker, which can be used in precise targeted GC therapy.
“…miRNAs are a group of non-coding RNAs with 20-23 nucleotides in length, which perform to modulate gene expression, principally by repressing transcription or degrading messenger RNA (mRNA), and the relevance of miRNAs in mediating the cascade of myocardial IRI has been underscored previously [9]. miR-219a-1-3p was found to be one of the ten downregulated miRNAs in coronary artery disease [10]. Besides, protocatechuic acid-induced miR-219a-5p expression ameliorated alcoholic liver disease by lowering p66shc-mediated formation of reactive oxygen species [11].…”
Myocardial infarction (MI) is a vital cause of death and disability globally. The primary treatment for diminishing acute myocardial ischemic injury is myocardial reperfusion, which may induce cardiomyocyte death. Our aim is to unravel the mechanism of sevoflurane (Sev) in microRNA-219a (miR-219a)-mediated regulation of absent in melanoma 2 (AIM2) and TLR4/MyD88 pathway during myocardial ischemia/reperfusion (I/R). The area of MI and apoptosis of cardiomyocytes of the developed mouse model were evaluated by TTC staining and TUNEL, respectively. After the determination of miR-219a as our target using microarray analysis, miR-219a atagomiR was used to treat the mouse model. The luciferase assay verified whether miR-219a targeted AIM2, and the miR-219a and AIM2 expression in myocardial tissues was detected by RT-qPCR and Western blot. miR-219a was significantly increased in myocardial tissues from mice treated with Sev, and the area of MI and cardiomyocyte apoptosis were decreased as a consequence. The miR-219a inhibitor reversed the action of Sev. Moreover, overexpression of AIM2 or induction of the TLR4 pathway aggravated myocardial I/R injury alleviated by miR-219a. All in all, the treatment of Sev upregulated miR-219a expression, which blocked the TLR4 pathway by targeting AIM2 and attenuated cardiomyocyte apoptosis in myocardial I/R mouse model.
“…1 ) previously associated to atherosclerotic acute myocardial infarction. [17] , [18] , [19] , [20] , [21] , [22] Confidence intervals (95%) of miRNAs in Fig. 1 are shown in Supplementary Table 2 Fig.…”
Section: Resultsmentioning
confidence: 99%
“…The comparison with other AT-AMI studies is a challenge mainly due to differences in normalization methods; nevertheless, our data show differences in the expression of miR-22-3p, miR-22-5p, miR-26b-5p, miR-30c-5p, miR-125b-5p, miR-106a-5p, and miR-191-5p, as previously reported. [17] , [18] , [19] , [20] , [21] , [22] …”
Background
Spontaneous Coronary Artery Dissection (SCAD) is an important cause of acute coronary syndromes, particularly in young to middle-aged women. Differentiating acute SCAD from coronary atherothrombosis remains a major clinical challenge.
Methods
A case-control study was used to explore the usefulness of circulating miRNAs to discriminate both clinical entities. The profile of miRNAs was evaluated using an unbiased human RT-PCR platform and confirmed using individual primers. miRNAs were evaluated in plasma samples from acute SCAD and atherothrombotic acute myocardial infarction (AT-AMI) from two independent cohorts; discovery cohort (SCAD
n
= 15, AT-AMI
n
= 15), and validation cohort (SCAD
n
= 11, AT-AMI
n
= 41) with 9 healthy control subjects. Plasma levels of IL-8, TGFB1, TGBR1, Endothelin-1 and MMP2 were analysed by ELISA assays.
Findings
From 15 differentially expressed miRNAs detected in cohort 1, we confirmed in cohort 2 the differential expression of 4 miRNAs: miR-let-7f-5p, miR-146a-5p, miR-151a-3p and miR-223-5p, whose expression was higher in SCAD compared to AT-AMI. The combined expression of these 4 miRNAs showed the best predictive value to distinguish between both entities (AUC: 0.879, 95% CI 0.72–1.0) compared to individual miRNAs. Functional profiling of target genes identified an association with blood vessel biology, TGF-beta pathway and cytoskeletal traction force. ELISA assays showed high plasma levels of IL-8, TGFB1, TGFBR1, Endothelin-1 and MMP2 in SCAD patients compared to AT-AMI.
Interpretation
We present a novel signature of plasma miRNAs in patients with SCAD. miR-let-7f-5p, miR-146a-5p, miR-151a-3p and miR-223-5p discriminate SCAD from AT-AMI patients and also shed light on the pathological mechanisms underlying this condition.
Funding
Spanish Ministry of Economy and Competitiveness (MINECO): Plan Nacional de Salud SAF2017-82886-R, Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV). Fundación BBVA a equipos de Investigación Científica 2018 and from Caixa Banking Foundation under the project code HR17-00016 to F.S.M. Instituto de Salud Carlos III (AES 2019): PI19/00565 to F.R, PI19/00545 to P.M. CAM (S2017/BMD-3671-INFLAMUNE-CM) from Comunidad de Madrid to FSM and PM. The UK SCAD study was supported by BeatSCAD, the British Heart Foundation (BHF) PG/13/96/30608 the NIHR rare disease translational collaboration and the Leicester NIHR Biomedical Research Centre.
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