Plasma small-extracellular vesicles enriched in miR-122-5p promote disease aggressiveness in pediatric Anaplastic Large Cell Lymphoma
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE209838 | GEO | 2023/08/08
REPOSITORIES: GEO
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Project description:Elite controllers maintain HIV-1 viral loads below the limit of detection. The mechanisms responsible for this phenomenon are poorly understood. As microRNAs (miRNAs) are regulators of gene expression and some of them modulate HIV infection, we have studied the miRNA profile in plasma from HIV elite controllers and chronically infected individuals and compared against healthy donors. Several miRNAs correlate with CD4+ T cell count or with the known time of infection. No significant differences were observed between elite controllers and healthy donors; however, 16 miRNAs were different in the plasma of chronic infected versus healthy donors. In addition, levels of hsa-miR-29b-3p, hsa-miR-33a-5p and hsa-miR-146a-5p were higher in plasma from elite controllers than chronic infected and hsa-miR-29b-3p and hsa-miR-33a-5p overexpression significantly reduced the viral production in MT2 cells. Therefore, levels of circulating miRNAs might be of diagnostic and/or prognostic value for HIV infection. Additionally, hsa-miR-29b-3p and miR-33a-5p may be used in therapeutic strategies. An exploratory cross-sectional study of microRNA levels in EDTA plasma samples. Plasma samples were obtained from 24 subjects and were classified in 3 groups, 9 Elite Controllers (defined as individuals with plasma viral load (PVL) < 50 copies/ml, CD4 count >350/ml), 9 chronic HIV patients (CH) under anti-retroviral treatment and 6 healthy HIV negative donors (HD). This study was approved by the HuM-CM-)sped Foundation Ethics Committee and informed consent was obtained from all subjects.
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Project description:Malignant germ-cell-tumours (GCTs) are characterised by microRNA (miRNA/miR-) dysregulation, with universal over-expression of miR-371~373 and miR-302/367 clusters regardless of patient age, tumour site, or subtype (seminoma/yolk-sac-tumour/embryonal carcinoma). These miRNAs are released into the bloodstream, presumed within extracellular-vesicles (EVs) and represent promising biomarkers. Here, we comprehensively examined the role of EVs, and their miRNA cargo, on (fibroblast/endothelial/macrophage) cells representative of the testicular GCT (TGCT) tumour microenvironment (TME). Small RNA next-generation-sequencing was performed on 34 samples, comprising representative malignant GCT cell lines/EVs and controls (testis fibroblast [Hs1.Tes] cell-line/EVs and testis/ovary samples). TME cells received TGCT co-culture, TGCT-derived EVs, and a miRNA overexpression system (miR-371a-OE) to assess functional relevance. TGCT cells secreted EVs into culture media. MiR-371~373 and miR-302/367 cluster miRNAs were overexpressed in all TGCT cells/subtypes compared with control cells and were highly abundant in TGCT-derived EVs, with miR-371a-3p/miR-371a-5p the most abundant. TGCT co-culture resulted in increased levels of miRNAs from the miR-371~373 and miR-302/367 clusters in TME (fibroblast) cells. Next, fluorescent labelling demonstrated TGCT-derived EVs were internalised by all TME (fibroblast/endothelial/macrophage) cells. TME (fibroblast/endothelial) cell treatment with EVs derived from different TGCT subtypes resulted in increased miR-371~373 and miR-302/367 miRNA levels, and other generic (eg, miR-205-5p/miR-148-3p) and subtype-specific (seminoma, eg, miR-203a-3p; yolk-sac-tumour, eg, miR-375-3p) miRNAs. MiR-371a-OE in TME cells resulted in increased collagen contraction (fibroblasts) and angiogenesis (endothelial cells), via direct mRNA downregulation and alteration of relevant pathways. TGCT cells communicate with nontumour stromal TME cells through release of EVs enriched in oncogenic miRNAs, potentially contributing to tumour progression.
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Project description:Circulating microRNAs are biomarkers reported to be stable and translational acrossspecies. miR-122 (miR-122-5p) is a hepatocyte-specific microRNA biomarker for drug-induced liver injury (DILI). Our objective was to develop an extraction-free andamplification-free detection method for measuring miR-122 that has translationalutility in context of DILI. We developed a single molecule dynamic chemical labelling(DCL) assay based on miR-122 hybridization to an abasic peptide nucleic acid probethat contained a reactive amine instead of a nucleotide at a specific position in thesequence. The single molecule DCL assay specifically measured miR-122 directly from10 μL of serum or plasma without any extraction steps, with a fit-for-purpose limit ofdetection of 1.32 pM. In 192 human serum samples, DCL accurately identified patientsat risk of DILI (area under ROC curve 0.98 (95%CI 0.96-1), P<0.0001). The miR-122assay also quantified liver injury in rats and dogs. When DCL beads were added toserum, the miR-122 signal was stabilised (no loss of signal after 14 days at roomtemperature). By contrast, there was substantial degradation of miR-122 in the absenceof beads (≈60% lost in 1 day). RNA sequencing demonstrated the presence of multiplemiR-122 isomiRs with DILI that were at low concentration or not present in healthypatient serum. Sample degradation over time produced more isomiRs, particularlyrapidly with DILI. PCR was inaccurate when analysing miR-122 isomiRs, whereas theDCL assay demonstrated accurate quantification. In summary, the DCL assay canaccurately measure miR-122 directly from serum and plasma to diagnose liver injury inhumans and other species, and can overcome important microRNA biomarker analyticaland biological challenges.
2019-11-23 | GSE140833 | GEO
Project description:BACKGROUND MicroRNAs (miRNAs) are small non-coding RNAs that recognize sites of complementarity of target messenger RNAs, resulting in transcriptional regulation and translational repression of target genes. In Huntington’s disease (HD), a neurodegenerative disease caused by a trinucleotide repeat expansion, miRNA dyregulation has been reported, which may impact gene expression and modify the progression and severity of HD. METHODS: We performed next-generation miRNA sequence analysis in prefrontal cortex (Brodmann Area 9) from 26 HD, 2 asymptomatic HD, and 36 control brains. Neuropathological information was available for all HD brains, including age at disease onset, CAG-repeat size, Vonsattel grade, and Hadzi-Vonsattel striatal and cortical scores, a continuous measure of the extent of neurodegeneration. Linear models were performed to examine the relationship of miRNA expression to these clinical features, and messenger RNA targets of associated miRNAs were tested for gene ontology term enrichment. RESULTS: We identified 75 miRNAs differentially expressed in HD brain (FDR q-value <0.05). Among the HD brains, nine miRNAs were significantly associated with Vonsattel grade of neuropathological involvement and three of these, miR-10b-5p, miR-10b-3p, and miR-302a-3p, significantly related to the Hadzi-Vonsattel striatal score (a continuous measure of striatal involvement) after adjustment for CAG length. Five miRNAs (miR-10b-5p, miR-196a-5p, miR-196b-5p, miR-10b-3p, and miR-106a-5p) were identified as having a significant relationship to CAG length-adjusted age of onset including miR-10b-5p, the mostly strongly over-expressed miRNA in HD cases. Although prefrontal cortex was the source of tissue profiled in these studies, the relationship of miR-10b-5p expression to striatal involvement in the disease was independent of cortical involvement. Correlation of miRNAs to the clinical features clustered by direction of effect and the gene targets of the observed miRNAs showed association to processes relating to nervous system development and transcriptional regulation. CONCLUSIONS: These results demonstrate that miRNA expression in cortical BA9 provides insight into striatal involvement and support a role for these miRNAs, particularly miR-10b-5p, in HD pathogenicity. The miRNAs identified in our studies of postmortem brain tissue may be detectable in peripheral fluids and thus warrant consideration as accessible biomarkers for disease stage, rate of progression, and other important clinical characteristics of HD. 26 Huntington's disease, 2 asymptomatic HD gene positive and 49 neurologically normal control prefrontal cortex samples
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Project description:BACKGROUND MicroRNAs (miRNAs) are small non-coding RNAs that recognize sites of complementarity of target messenger RNAs, resulting in transcriptional regulation and translational repression of target genes. In Huntington’s disease (HD), a neurodegenerative disease caused by a trinucleotide repeat expansion, miRNA dyregulation has been reported, which may impact gene expression and modify the progression and severity of HD. METHODS: We performed next-generation miRNA sequence analysis in prefrontal cortex (Brodmann Area 9) from 26 HD, 2 asymptomatic HD, and 36 control brains. Neuropathological information was available for all HD brains, including age at disease onset, CAG-repeat size, Vonsattel grade, and Hadzi-Vonsattel striatal and cortical scores, a continuous measure of the extent of neurodegeneration. Linear models were performed to examine the relationship of miRNA expression to these clinical features, and messenger RNA targets of associated miRNAs were tested for gene ontology term enrichment. RESULTS: We identified 75 miRNAs differentially expressed in HD brain (FDR q-value <0.05). Among the HD brains, nine miRNAs were significantly associated with Vonsattel grade of neuropathological involvement and three of these, miR-10b-5p, miR-10b-3p, and miR-302a-3p, significantly related to the Hadzi-Vonsattel striatal score (a continuous measure of striatal involvement) after adjustment for CAG length. Five miRNAs (miR-10b-5p, miR-196a-5p, miR-196b-5p, miR-10b-3p, and miR-106a-5p) were identified as having a significant relationship to CAG length-adjusted age of onset including miR-10b-5p, the mostly strongly over-expressed miRNA in HD cases. Although prefrontal cortex was the source of tissue profiled in these studies, the relationship of miR-10b-5p expression to striatal involvement in the disease was independent of cortical involvement. Correlation of miRNAs to the clinical features clustered by direction of effect and the gene targets of the observed miRNAs showed association to processes relating to nervous system development and transcriptional regulation. CONCLUSIONS: These results demonstrate that miRNA expression in cortical BA9 provides insight into striatal involvement and support a role for these miRNAs, particularly miR-10b-5p, in HD pathogenicity. The miRNAs identified in our studies of postmortem brain tissue may be detectable in peripheral fluids and thus warrant consideration as accessible biomarkers for disease stage, rate of progression, and other important clinical characteristics of HD.
2015-03-12 | GSE64977 | GEO
Project description:We contrasted innate and adaptive immune responses elicited by the DNA/ALVAC/gp120/alum vaccine in non-human primates differing in age. We performed several analyses. MicroRNA profiling in Extracellular Vesicles (EVs) isolated from plasma collected prior and 1 week following vaccination identified 109 miRNAs that differed significantly between age groups at the end of immunization. Several miRNAs correlated with risk of virus acquisition in young and old animals, but none remained significant following correction for FDR. In young animals, we identified 3 miRNAs which were modified by vaccination and correlated with decreased risk of SIV acquisition (unadjusted p-values). Of these three miRNAs, two, miR-139-5p and miR-29b-1-5p, were increased by vaccination, whereas one, mir 98, decreased by vaccination. MiR-139-5p has several validated targets, including: CXCR4, important for egress of CXCR4+ cells and monocytes from bone marrow and HIV entry in target T-cells; the cAMP-specific PDE4D gene which decreases CREB1-mediated transcription by degrading cAMP; and the IGF-1/AKT/Glut1 gene receptor, central for glucose utilization and cellular metabolism. The validated target of miR-29b-1-5p is the NF-kB pathway. Mir-98 has several validated targets, inhibits IL-10 production, modulates M1-M2 polarization of macrophages towards the M1 phenotype, and its CCL2-induced downregulation increases IL-6 production. These data suggest the importance of CREB1-mediated transcription in vaccine efficacy, identified in the study, is likely assisted by miR-139-5p targeting the cAMP-degrading PDE4D gene, and downregulation of the NF-kB pathway, targeted by miR-29b-1-5p.
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