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MicroRNA-mRNA expression profiles associated with medulloblastoma subgroup 4.

ABSTRACT: Purpose:Medulloblastoma (MB), the most common malignant brain tumor in children, is divided into four tumor subgroups: wingless-type (WNT), sonic hedgehog (SHH), Group 3, and Group 4. Ideally, clinical practice and treatment design should be subgroup specific. While WNT and SHH subgroups have well-defined biomarkers, distinguishing Group 3 from Group 4 is not straightforward. MicroRNAs (miRNAs), which regulate posttranscriptional gene expression, are involved in MB tumorigenesis. However, the miRNA-messenger RNA (mRNA) regulatory network in MB is far from being fully understood. Our aims were to investigate miRNA expression regulation in MB subgroups, to assess miRNA target relationships, and to identify miRNAs that can distinguish Group 3 from Group 4. Patients and methods:With these aims, integrated transcriptome mRNA and miRNA expression analysis was performed on primary tumor samples collected from 18 children with MB, using miRNA sequencing (miRNA-seq), RNA sequencing (RNA-seq), and quantitative PCR. Results:Of all the expressed miRNAs, 19 appeared to be significantly differentially expressed (DE) between Group 4 and non-Group 4 subgroups (false discovery rate [FDR] <0.05), including 10 miRNAs, which, for the first time, are reported to be in conjunction with MB. RNA-seq analysis identified 165 genes that were DE between Group 4 and the other subgroups (FDR <0.05), among which seven are predicted targets of five DE miRNAs and exhibit inverse expression pattern. Conclusion:This study identified miRNA molecules that may be involved in Group 4 etiology, in general, and can distinguish between Group 3 and Group 4, in particular. In addition, understanding the involvement of miRNAs and their targets in MB may improve diagnosis and advance the development of targeted treatment for MB.

SUBMITTER: Gershanov S

PROVIDER: S-EPMC5818864 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Project description:Medulloblastoma (MB) is one of the most common malignant pediatric brain tumor. The aim of our study was to understand which mechanisms are involved in aberrant activation of Wnt pathway and its association with MB tumor development. We studied the expression profiles of 19 MBs tumors using a genome-wide approach, furthermore we have included the data obtained from four independent public Datasets of gene expression (see README file below) to increase the statistical power of the study. The expression profiles identified the Wnt inhibitor gene, DKK3, significant down-regulated. DKK3 down-regulation was confirmed by qPCR in 80% of samples (27/33 MB tumors and in 3/5 MB human cell lines). Since DKK3 was found methylated in several cancers we also investigated the status of methylated CpG sites within the three promoters by a combination of two approaches: the MSP and pyrosequencing. MSP showed no methylation in all promoters while the pyrosequencing, a quantitative technique, indicated a very low level of methylation. To verify the epigenetic involvement on DKK3 silencing, we also studied the effect of Trichostatin A (TSA) in 4 MB cell lines (DAOY; D283; D425; D458). After TSA treatment we observed a significant DKK3 mRNA expression increase in 3/4 cell lines compared to the no treated cells. DAOY cells, that have a normal DKK3 expression value, did not change significantly the DKK3 expression after TSA treatment. To further validate the role of histone tail modifications as an epigenetic silencing mechanism for DKK3 in MB, we performed Chromatin Immunoprecipitation (ChIP) experiment using antibodies against acetylated histones. According to our earlier results, TSA treatment increased the signal of the histone modification meH3K4 which is related to a transcriptionally active gene respect to the untreated controls. Finally, we evaluated the DKK3 protein in three MB cell lines (DAOY; D283; D425) after 24h of TSA treatment, by immunofluorescence. We analysed 19 Medulloblastoma tumor from pediatric patients, a commercial pool (Clontech) of 24 normal cerebellum from female and male Caucasians (ages: 16-70 years; cause of death: sudden death) and a pool of 10 normal cerebellum from children (6 Caucasians and 4 African Americans; ages: 0-16 years; cause of death: sudden death) using 44K whole genome oligonucleotids microarray

Project description:ObjectiveTo evaluate the specificity of expression patterns of cell-free circulating microRNAs (miRNAs) in systemic lupus erythematosus (SLE).MethodsTotal RNA was purified from plasma, and 45 different specific, mature miRNAs were determined using quantitative reverse transcription-polymerase chain reaction assays. A total of 409 plasma samples were obtained from 364 different patients with SLE, healthy control subjects, and control subjects with other autoimmune diseases. The results in the primary cohort of 62 patients with SLE and 29 healthy control subjects were validated in 2 independent cohorts: a validation cohort comprising 68 patients with SLE and 68 healthy control subjects, and a disease control cohort comprising 20 patients with SLE (19 of whom were from the other validation cohort), 46 healthy control subjects, 38 patients with vasculitis, 18 patients with rheumatoid arthritis, and 20 immunosuppressed patients.ResultsSeven miRNAs were statistically significantly differentially expressed in plasma from patients with SLE. The expression of miRNA-142-3p (miR-142-3p) and miR-181a was increased, and the expression of miR-106a, miR-17, miR-20a, miR-203, and miR-92a was decreased. In addition, the expression of miR-342-3p, miR-223, and miR-20a was significantly decreased in SLE patients with active nephritis. A predictive model for SLE based on 2 or 4 miRNAs differentiated patients with SLE from control subjects (76% accuracy) when validated independently (P < 2 × 10(-9) ). Use of the 4-miRNA model provided highly significant differentiation between the SLE group and disease controls, except for those with vasculitis.ConclusionCirculating miRNAs are systematically altered in SLE. A 4-miRNA signature was diagnostic of SLE, and a specific subset of miRNA profiles was associated with nephritis. All of the signature miRNAs target genes in the transforming growth factor β signaling pathways. Other targets include regulation of apoptosis, cytokine-cytokine receptors, T cell development, and cytoskeletal organization. These findings highlight possible dysregulated pathways in SLE and suggest that circulating miRNA patterns distinguish SLE from other immunoinflammatory phenotypes.

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MicroRNA-mRNA expression profiles associated with medulloblastoma subgroup 4.

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