High-throughput microRNA profile in adult and pediatric primary glioblastomas: the role of miR-10b-5p and miR-630 in the tumor aggressiveness
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE158284 | GEO | 2020/09/22
REPOSITORIES: GEO
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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. 26 Huntington's disease, 2 asymptomatic HD gene positive and 49 neurologically normal control prefrontal cortex samples
2015-03-12 | E-GEOD-64977 | biostudies-arrayexpress
Project description:Background/ Aim: Diabetes has substantive co-occurrence with disorders of gut-brain interactions (DGBIs). The pathophysiological and molecular mechanisms linking diabetes and DGBIs are unclear. miRNAs are key regulators of diabetes and gut dysmotility. We investigated whether impaired gut barrier function regulated by a key miRNA, miR-10b-5p, links diabetes and gut dysmotility. Methods: We created a new mouse line using the Mb3Cas12a/Mb3Cpf1 endonuclease to knock out mir-10b globally. Loss of function studies were conducted to characterize diabetes, gut dysmotility, and gut barrier dysfunction phenotypes in these mice. Gain of function studies were conducted by injecting these mice with a miR-10b-5p mimic. Further, we performed miRNA-sequencing analysis from colonic mucosa from mir-10b KO, WT, and miR-10b-5p mimic injected mice to confirm 1) deficiency of miR-10b-5p in KO mice, and 2) restoration of miR-10b-5p expression after the mimic injection. Results: Congenital loss of mir-10b in mice led to the development of hyperglycemia, gut dysmotility, and gut barrier dysfunction. We found increased gut permeability and reduced expression of the tight junction protein Zonula occludens-1 (ZO-1), in the colon of mir-10b KO mice. We further confirmed that patients with diabetes or IBS-C, a known DGBI that is linked to leaky gut, had significantly reduced miR-10b-5p expression. Injection of a miR-10b-5p mimic in mir-10b KO mice rescued these molecular alterations and phenotypes. Conclusion: Our study uncovered a potential pathophysiologic mechanism of gut barrier dysfunction that links both the diabetes and gut dysmotility phenotypes in mice lacking miR-10b-5p. Treatment with a miR-10b-5p mimic reversed the leaky gut, diabetic, and gut dysmotility phenotypes, highlighting the translational potential of miR-10b-5p mimic.
2023-07-13 | GSE236981 | GEO
Project description:Applying Next Generation Sequencing technique we compared the miRNA expression pattern of tumor tissue sample of 6 GPs and peritumoral region of 6 lower grade (I-II) Glioma patients, serving as control group. To determine the difference on miRNA expresion level between GBM and control cases, we performed cluster analysis on the NGS dataset of 6 replicates for each of the two goups of samples with iDEP 96 software. In order to characterize the extent of up- or downregulation, log2FC values were calculated using the iDEP.96 web tool applying the DESeq2 algorithm. On the base of that 117 known miRNAs were identified to be differentially expressed using a threshold of false discovery rate (FDR) <0.05 and fold-change> 2 during the analysis. Among them, 35 miRNAs were upregulated (log2FC > 2) and 82 miRNAs were downregulated (log2FC < -2) with biological revelance in tissue samples comparing with the control samples. To validate our results obtained by NGS, five upregulated miRNAs: hsa-miR-196a-5p, hsa-miR-21-3p, hsa-miR-92b-5p, hsa-miR-10b-3p, hsa-miR-503-5p and three downregulated miRNAs: hsa-mir-383-5p, hsa-mir-490-3p, hsa-mir-1224-3p were chosen for RT-qPCR analysis. As the result of that hsa-miR-196a-5p, hsa-miR-21-3p, and hsa-miR-10b-3p was significantly upregulated while hsa-mir-383-5p and hsa-mir-490-3p was significantly downregulated, compared with those in the control samples. The other three miRNAs: hsa-miR-1224-3p, hsa-miR-92b-5p, hsa-miR-503-5p did not show significant difference between the control group and GPs.
2024-10-31 | GSE244332 | 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.
2015-03-12 | GSE64977 | 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:Background: Glioblastoma multiforme (GBM) is the most aggressive and most lethal primary malignant brain tumor, correlated with survival rates of less than one year from the time of diagnosis. Current surgical procedure attempts to remove the bulk of the tumor mass, whereas GBM frequently recurs within 1-3cm from the primary tumor resection site. Molecular mechanisms involved in the recurrence of the tumor are still poorly understood. The aim of the study was to define the molecular signature of GBM surrounding white matter (WM) in order to better understand the molecular mechanisms involved with tumor relapse. Material & Methods: Human GBM tumor bulk and surrounding tissue (1-3cm from the border of the tumor) were obtained from five patients who underwent total tumour resection, while normal white matter was harvested from patients who underwent surgical procedure for nonmalignant pathologies. Samples were processed for hybridization on the Affymetrix Human U133A arrays and data were examined with the GeneSpring analysis software. Results: Gene expression analysis of the samples was done in 2 independent steps. First, molecular profiling comparison of GBM surrounding WM and normal WM resulted in 59 genes differentially expressed between both tissues. Among these, numerous genes expressed by mature neural cells were down-regulated in GBM surrounding WM, while gene products supporting invasion were overexpressed. Moreover, KLRC1, a specific natural killer receptor naturally involved in the activation of antitumoral cells was drastically repressed in GBM surrounding WM, suggesting that the antitumoral immune surveillance is compromised in this tissue. Second, we focused our study on genes specifically regulated in GBM periphery respectively to GBM core. The highest up-regulated gene in GBM surrounding tissue encodes for DTX4, a regulator of NOTCH signalling pathway described for its key role in maintaining neural progenitors in an uncommitted state. Conclusion: This study revealed unique molecular characteristics of GBM surrounding tissue, showing the dysregulation of genes involved in immune surveillance along with genes associated to stemness maintenance. All together, these data may help to understand the molecular mechanisms associated with GBM recurrence This study attempted to define the molecular characteristics of the GBM surrounding tissue. To this end, GBM tumor samples were obtained from 5 patients who underwent total tumor resection. Surrounding tumor mass tissue was retrieved in all cases from not infiltrated white matter sited at 2 cm from the macroscopic tumor border. Furthermore, control white matter biopsies were harvested from patients operated on for deep intracerebral cavernomas. Each sample was hybridized onto Affymetrix human U133 arrays. For each patient, tumor core sample and surrounding tissue were harvested and are identified with the same suffix number. In 2 cases, (patients 3 and 4), two tumor peripheral tissue samples were harvested and are identified with the same number followed by "R" (replicate).
2009-06-15 | E-GEOD-13276 | biostudies-arrayexpress
Project description:Previously, we used mouse and non-human primate models to show that serum miRNAs may predict the biological impact of lethal and sublethal radiation doses. We hypothesized that these results can be replicated in humans treated with total body irradiation (TBI), and that miRNAs may be used as clinically feasible biodosimeters. To test this hypothesis, serial serum samples were obtained from 25 patients who underwent allogeneic stem-cell transplantation and profiled for miRNA expression using next-generation sequencing. Differential expression results were largely consistent with previous studies and allowed us to select miRNAs, including miR-150-5p, miR-126-5p, miR-375, miR-215-5p, miR-144-5p, miR-122-5p, miR-320d and miR-10b-5p to build classifiers using qPCR-based quantification. We therefore conclude that serum miRNAs reflect radiation exposure and dose for humans undergoing TBI and may be used as functional biodosimeters for precise identification of people exposed to clinically significant radiation doses.
2021-05-20 | GSE174705 | GEO
Project description:Glioblastoma (GBM) is a deadly and the most common primary brain tumor in adults. Due to their regulation of a high number ofmRNA transcripts, microRNAs (miRNAs) are key molecules in the control of biological processes and are thereby promisingtherapeutic targets for GBM patients. In this regard, we recently reported miRNAs as strong modulators of GBM aggressiveness.Here, using an integrative and comprehensive analysis of the TCGA database and the transcriptome of GBM biopsies, we identifiedthree critical and clinically relevant miRNAs for GBM, miR-17-3p, miR-222, and miR-340. In addition, we showed that thecombinatorial modulation of three of these miRNAs efficiently inhibited several biological processes in patient-derived GBM cells ofall these three GBM subtypes (Mesenchymal, Proneural, Classical), induced cell death, and delayed tumor growth in a mouse tumormodel. Finally, in a doxycycline-inducible model, we observed a significant inhibition of GBM stem cell viability and a significantdelay of orthotopic tumor growth. Collectively, our results reveal, for the first time, the potential of miR-17-3p, miR-222 and miR-340multi-targeting as a promising therapeutic strategy for GBM patients.Cell Death and Disease (2023) 14:630 ; https://doi.org/10.1038/s41419-023-06117-z
2023-11-03 | GSE246708 | GEO
Project description:Background: Patients with glioblastoma (GBM) have a dramatically poor prognosis. The recent REGOMA trial suggested an overall survival benefit of regorafenib in recurrent GBM patients. Considering the extreme genetic heterogeneity of GBMs, we aimed to identify molecular biomarkers predictive of differential response to the drug. The study provides evidence that a signature based on the expression of five biomarkers could help identifying a subgroup of GBM patients exhibiting a striking survival advantage when treated with regorafenib. Despite the presented results must be confirmed in larger replication cohorts, the study highlights potential biomarker options to help guiding the clinical decision among regorafenib and other treatments in patients with relapsing GBM. Methods.Total RNA was extracted from tumor samples of patients enrolled in the REGOMA trial. Genome-wide transcriptome and miRNA profiles were associated with patients' Overall Survival (OS) and Progression Free Survival (PFS). Results. At first step, a set of 11 gene transcripts (HIF1A, CTSK, SLC2A1, KLHL12, CDKN1A, CA12, WDR1, CD53, CBR4, NIFK-AS1, RAB30-DT) and 10 miRNAs (miR-93-5p, miR-203a-3p, miR-17-5p, let-7c-3p, miR-101-3p, miR-3607-3p, miR-6516-3p, miR-301a-3p, miR-23b-3p, miR-222-3p) was filtered by comparing survival between regorafenib and lomustine arms. As second step, a minisignature of two gene transcripts (HIF1A, CDKN1A) and three miRNAs (miR-3607-3p, miR-301a-3p, miR-93-5p) identified a subgroup of patients showing prolonged survival after regorafenib administration (median OS range 10.6 - 20.8 months). Conclusions. The study provides evidence that a signature based on the expression of five biomarkers could help identifying a subgroup of GBM patients exhibiting a striking survival advantage when treated with regorafenib. Despite the presented results must be confirmed in larger replication cohorts, the study highlights potential biomarker options to help guiding the clinical decision among regorafenib and other treatments in patients with relapsing GBM.
2020-12-31 | GSE154042 | GEO
Project description:Background: Patients with glioblastoma (GBM) have a dramatically poor prognosis. The recent REGOMA trial suggested an overall survival benefit of regorafenib in recurrent GBM patients. Considering the extreme genetic heterogeneity of GBMs, we aimed to identify molecular biomarkers predictive of differential response to the drug. The study provides evidence that a signature based on the expression of five biomarkers could help identifying a subgroup of GBM patients exhibiting a striking survival advantage when treated with regorafenib. Despite the presented results must be confirmed in larger replication cohorts, the study highlights potential biomarker options to help guiding the clinical decision among regorafenib and other treatments in patients with relapsing GBM. Methods.Total RNA was extracted from tumor samples of patients enrolled in the REGOMA trial. Genome-wide transcriptome and miRNA profiles were associated with patients' Overall Survival (OS) and Progression Free Survival (PFS). Results. At first step, a set of 11 gene transcripts (HIF1A, CTSK, SLC2A1, KLHL12, CDKN1A, CA12, WDR1, CD53, CBR4, NIFK-AS1, RAB30-DT) and 10 miRNAs (miR-93-5p, miR-203a-3p, miR-17-5p, let-7c-3p, miR-101-3p, miR-3607-3p, miR-6516-3p, miR-301a-3p, miR-23b-3p, miR-222-3p) was filtered by comparing survival between regorafenib and lomustine arms. As second step, a minisignature of two gene transcripts (HIF1A, CDKN1A) and three miRNAs (miR-3607-3p, miR-301a-3p, miR-93-5p) identified a subgroup of patients showing prolonged survival after regorafenib administration (median OS range 10.6 - 20.8 months). Conclusions. The study provides evidence that a signature based on the expression of five biomarkers could help identifying a subgroup of GBM patients exhibiting a striking survival advantage when treated with regorafenib. Despite the presented results must be confirmed in larger replication cohorts, the study highlights potential biomarker options to help guiding the clinical decision among regorafenib and other treatments in patients with relapsing GBM.
2020-12-31 | GSE154041 | GEO