MiR-93-5p is a bona fide Oncodriver Targeting both Classical and Epigenetic Tumor Suppressive Pathways in Liver Cancer
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE93553 | GEO | 2019/01/12
REPOSITORIES: GEO
Similar Datasets
Project description:Sepsis remains a leading cause of death and currently has no pathogenesis-specific therapy. Hampered progress is partly due to the lack of insight into deep mechanistic processes. Deciphering the functions of microRNAs in sepsis pathogeny became a dynamic research topic in the last decade. To screen for new microRNA targets for sepsis therapeutics, we used human samples: microRNA array data from peripheral blood mononuclear cells (PBMCs) from sepsis patients and controls, whole blood samples from sepsis survivors; and multiple animal models: mouse cecum ligation-puncture (CLP)-induced sepsis, mouse viral microRNA challenge, and baboon Gram-positive and Gram-negative sepsis models. miR-93-5p met the criteria for a therapeutic target, being overexpressed in baboons which died early after induction of sepsis and downregulated in humans who survived after sepsis. Therapeutically, inhibiting miR-93-5p prolonged the overall survival of mice with CLP-induced sepsis, with a stronger effect in old mice. Mechanistically, anti-miR-93-5p therapy reduced inflammatory monocytes and increased circulating effector memory T cells, especially CD4+ subset. Ago2-immunoprecipitation in miR-93-knockout T cells identified important regulatory receptors, CD28 and CD160, as direct miR-93-5p target genes. In conclusion, miR-93-5p is a potential therapeutic target in sepsis in the elderly through its regulation of both innate and adaptive immunity. We applied the Ago2-RIP Chip (Ribonucleoprotein ImmunoPrecipitation followed by microarray analysis) to identify miR-93-5p target mRNAs. This methodology uses beads coupled to either anti-Ago2 antibody (or an IgG control) to pull down the RISC complex together with any miRNA-interacting mRNAs. To define target genes of miR-93-5p, we assessed mRNA transcripts enriched in the Ago2-IP fraction of JURKAT parental cells or control cells (where miR-93-5p is present) but not in the two KO clones (where miR-93-5p is absent) by microarray
2023-06-13 | GSE223458 | GEO
Project description:miR-93-5p controls endothelial glycolysis and proliferation
2017-11-01 | GSE86497 | GEO
Project description:miR-93 is often dysregulated in several tumor cell lines, including lymphoblastic leukemias. This dataset can represent a further insight into gene expression changes and GO Terms associated with miR-93 over-expression. miR-93 was over-expressed in Jurkat cells by transduction with a lentiviral transgenic construct encoding for miR-93 under a PGK promoter. A cognate vector encoding for a control hairpin was used to generate control cell line. mRNA Microarray gene expression profiling of Jurkat cells tranduced with either a miR-93 sponge or control construct. 3 biological replicas have been performed.
2016-03-21 | E-MTAB-4588 | biostudies-arrayexpress
Project description:Here we studied the role of oxidized phospholipids in mediating phenotype switching of endothelial cells between quiescent and angiogenic states. Two oxPAPC datasets, a microRNA array and global run-on sequencing (GRO-seq), was combined with Nuclear factor erythroid 2-Related Factor 2 (NRF2) binding model to select candidate miRNAs for further studies. The pre-screening resulted in a selection of miR-106b~25 cluster for further studies. The cluster was shown to be both oxPAPC-responsive and NRF2-regulated, and its diagnostic and prognostic potential was investigated in pericardial fluid samples of heart failure and atherosclerosis patients. As the most abundant member of the cluster in both endothelial cells and pericardial fluid of atherosclerosis patients, miR-93-5p was selected for more detailed studies. RNA-seq from miR-93 overexpressing cells revealed significant changes in pathways related to angiogenesis. Together with NRF2, miR-93 was shown to control endothelial plasticity through regulation of the key players, namely Krüppel-like factor 2 (KLF2) for quiescence, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) for glycolysis, and Vascular Endothelial Growth Factor A (VEGFA), Forkhead box protein O1 (FOXO1) and MYC proto-oncogene protein (MYC) for growth and proliferation.The findings show that NRF2 and miR-93 control the activity of endothelial cells and mediate the effects of oxPAPC on endothelial activation, collectively providing novel mechanisms for the control of endothelial plasticity and oxPAPC response.
2017-11-01 | GSE103530 | GEO
Project description:miR-93 and 135b were transfected at 50nM in mouse embryonic fibroblasts (MEFs). Total RNAs were extracted at 48hrs post transfection and mRNA expression was then analyzed.
2015-09-12 | E-MTAB-2931 | biostudies-arrayexpress
Project description:Myocardial regeneration is restricted to early postnatal life, when mammalian cardiomyocytes still retain the ability to proliferate. The molecular cues that induce cell cycle arrest of neonatal cardiomyocytes towards terminally differentiated adult heart muscle cells remain obscure. We report that the miR-106b~25cluster is higher expressed in the early postnatal myocardium and decreases in expression towards adulthood, especially under conditions of overload, and orchestrates the transition of cardiomyocyte hyperplasia towards cell cycle arrest and hypertrophy by virtue of its targetome. To identify the relevant targets of individual miRNAs in the miR-106b~15 cluster and elucidate the molecular mechanisms underlying the proliferative effects of this microRNA cluster, we assessed the global transcriptomic changes by deep-sequencing total neonatal mouse cardiomyocyte RNA after exogeneous transfection with hsa-miR-106b-5p, hsa-miR-93-5p, hsa-miR-25-3p and compared the transcriptomic profiles to cardiomyocytes transfected with cel-miR-67, a control miRNA.
2021-06-25 | GSE178867 | GEO
Project description:MiRNAs regulate posttranscriptional gene expression and are widely implicated in the pathogenesis of complex diseases. We aim to elucidate miRNA regulation of the atrial mRNA signatures that associate with AF. This may provide novel mechanistical insights and candidate targets for therapies using miRNA mimics or antimiRs.
We present combined miRNAs-mRNAs sequencing in atrial tissues of patient without AF (n=22), with paroxysmal AF (n=22) and with persistent AF (n=20). MiRNA and mRNA signatures followed an ordinal scale from nonAF to paroxysmal to persistent AF patients. The previously reported mRNA sequencing identified 5228 differentially expressed genes involved in epithelial to mesenchymal transition, endothelial cell proliferation and extracellular matrix remodelling involving collagens, glycoproteins and proteoglycans. We discovered 103 differentially expressed miRNAs. Key downregulated miRNAs included miR-135b-5p, miR-138-5p, miR-200a-3p, miR-200b-3p and miR-31-5p and key upregulated miRNAs were miR-144-3p, miR-15b-3p, miR-182-5p miR-18b-5p, miR-4306 and miR-206. The expression levels of differentially expressed miRNAs were negatively correlated with the expression levels of their predicted target mRNAs. The downregulated miRNAs demonstrated a more profound transcriptome effect than the upregulated miRNAs. Upregulated biological processes enriched in miRNAs targets related to epithelial and endothelial cell migration and glycosaminoglycan biosynthesis, in line with the processes discovered by the mRNA sequencing analysis.
Combined analysis of miRNA and mRNA sequencing uncovered miRNAs with a broad transcriptional effect in human AF. Epithelial to mesenchymal transition and endothelial cell proliferation were processes controlled by downregulated miR-135b-5p, miR-138-5p, miR-200a-3p, miR-200b-3p and miR-31-5p, which in turn may contribute to (myo)fibroblast activation and structural remodeling.\
| EGAS00001005296 | EGA
Project description:Extracorporeal photochemotherapy (ECP) is employed for the management of cutaneous T cell lymphoma (CTCL). ECP involves the extracorporeal exposure of white blood cells (WBCs) to a photosensitizer, 8-methoxypsoralen (8-MOP), in the context of ultraviolet A (UVA) radiation, followed by WBC reinfusion. Historically, the therapeutic activity of ECP has been attributed to selective cytotoxicity on circulating CTCL cells. However, only a fraction of WBCs is exposed to ECP, and 8-MOP is inactive in the absence of UVA light, implying that other mechanisms underlie the anticancer effects of ECP. Recently, ECP has been shown to enable the physiological differentiation of monocytes into dendritic cells (DCs) that efficiently cross-present tumor-associated antigens (TAAs) to CD8+ T lymphocytes to initiate cognate immunity. However, the source of TAAs and immunostimulatory signals for such DCs remains to be elucidated. Here, we demonstrate that 8-MOP plus UVA light reduces melanoma cell viability along with the emission of ICD-associated danger signals including calreticulin (CALR) exposure on the cell surface and secretion of ATP, high mobility group box 1 (HMGB1) and type I interferon (IFN). Consistently, melanoma cells succumbing to 8-MOP plus UVA irradiation are efficiently engulfed by monocytes, ultimately leading to cross-priming of CD8+ T cells against cancer. Moreover, malignant cells killed by 8-MOP plus UVA irradiation in vitro vaccinate syngeneic immunocompetent mice against living cancer cells of the same type, and such a protection is lost when cancer cells are depleted of calreticulin or HMGB1, as well as in the presence of an ATP-degrading enzyme or antibodies blocking type I IFN receptors. ECP induces bona fide ICD, hence simultaneously providing monocytes with abundant amounts of TAAs and immunostimulatory signals that are sufficient to initiate cognate anticancer immunity.
| S-EPMC6675789 | biostudies-literature
Project description:UnlabelledMammalian prions are PrP proteins with altered structures causing transmissible fatal neurodegenerative diseases. They are self-perpetuating through formation of beta-sheet-rich assemblies that seed conformational change of cellular PrP. Pathological PrP usually forms an insoluble protease-resistant core exhibiting beta-sheet structures but no more alpha-helical content, loosing the three alpha-helices contained in the correctly folded PrP. The lack of a high-resolution prion structure makes it difficult to understand the dynamics of conversion and to identify elements of the protein involved in this process. To determine whether completeness of residues within the protease-resistant domain is required for prions, we performed serial deletions in the helix H2 C terminus of ovine PrP, since this region has previously shown some tolerance to sequence changes without preventing prion replication. Deletions of either four or five residues essentially preserved the overall PrP structure and mutant PrP expressed in RK13 cells were efficiently converted into bona fide prions upon challenge by three different prion strains. Remarkably, deletions in PrP facilitated the replication of two strains that otherwise do not replicate in this cellular context. Prions with internal deletion were self-propagating and de novo infectious for naive homologous and wild-type PrP-expressing cells. Moreover, they caused transmissible spongiform encephalopathies in mice, with similar biochemical signatures and neuropathologies other than the original strains. Prion convertibility and transfer of strain-specific information are thus preserved despite shortening of an alpha-helix in PrP and removal of residues within prions. These findings provide new insights into sequence/structure/infectivity relationship for prions.ImportancePrions are misfolded PrP proteins that convert the normal protein into a replicate of their own abnormal form. They are responsible for invariably fatal neurodegenerative disorders. Other aggregation-prone proteins appear to have a prion-like mode of expansion in brains, such as in Alzheimer's or Parkinson's diseases. To date, the resolution of prion structure remains elusive. Thus, to genetically define the landscape of regions critical for prion conversion, we tested the effect of short deletions. We found that, surprisingly, removal of a portion of PrP, the C terminus of alpha-helix H2, did not hamper prion formation but generated infectious agents with an internal deletion that showed characteristics essentially similar to those of original infecting strains. Thus, we demonstrate that completeness of the residues inside prions is not necessary for maintaining infectivity and the main strain-specific information, while reporting one of the few if not the only bona fide prions with an internal deletion.
| S-EPMC4944278 | biostudies-literature
Project description:Sporadic Creutzfeldt-Jakob disease (sCJD) presents as a rapidly progressive dementia which is usually fatal within six months. No clinical blood tests are currently available for diagnosis or disease monitoring. Here, we profiled blood microRNA (miRNA) expression in sCJD. Small RNA-sequencing of 57 sCJD patients and 48 healthy controls revealed differential expression of hsa-let-7i-5p, hsa-miR-16-5p, hsa-miR-93-5p and hsa-miR-106b-3p. Downregulation of hsa-let-7i-5p, hsa-miR-16-5p and hsa-miR-93-5p replicated in an independent cohort using quantitative PCR, with concomitant upregulation of four of their mRNA targets. Absence of correlation in cross-sectional analysis with clinical phenotypes paralleled the lack of association between rate of decline in miRNA expression and rate of disease progression in a longitudinal cohort of 50 samples from 21 sCJD patients. Finally, the miRNA signature showed a high level of accuracy in discriminating sCJD from Alzheimer’s disease (AD). These findings highlight novel molecular alterations in the periphery in sCJD which can provide information about differential diagnosis and improve mechanistic understanding of human prion diseases.
2020-01-13 | GSE140069 | GEO