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Posttranscriptional deregulation of signaling pathways in meningioma subtypes by differential expression of miRNAs.

ABSTRACT: Micro (mi)RNAs are key regulators of gene expression and offer themselves as biomarkers for cancer development and progression. Meningioma is one of the most frequent primary intracranial tumors. As of yet, there are limited data on the role of miRNAs in meningioma of different histological subtypes and the affected signaling pathways.In this study, we compared expression of 1205 miRNAs in different meningioma grades and histological subtypes using microarrays and independently validated deregulation of selected miRNAs with quantitative real-time PCR. Clinical utility of a subset of miRNAs as biomarkers for World Health Organization (WHO) grade II meningioma based on quantitative real-time data was tested. Potential targets of deregulated miRNAs were discovered with an in silico analysis.We identified 13 miRNAs deregulated between different subtypes of benign meningiomas, and 52 miRNAs deregulated in anaplastic meningioma compared with benign meningiomas. Known and putative target genes of deregulated miRNAs include genes involved in epithelial-to-mesenchymal transition for benign meningiomas, and Wnt, transforming growth factor-?, and vascular endothelial growth factor signaling for higher-grade meningiomas. Furthermore, a 4-miRNA signature (miR-222, -34a*, -136, and -497) shows promise as a biomarker differentiating WHO grade II from grade I meningiomas with an area under the curve of 0.75.Our data provide novel insights into the contribution of miRNAs to the phenotypic spectrum in benign meningiomas. By deregulating translation of genes belonging to signaling pathways known to be important for meningioma genesis and progression, miRNAs provide a second in line amplification of growth promoting cellular signals. MiRNAs as biomarkers for diagnosis of aggressive meningiomas might prove useful and should be explored further in a prospective manner.

SUBMITTER: Ludwig N

PROVIDER: S-EPMC4588755 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Posttranscriptional deregulation of signaling pathways in meningioma subtypes by differential expression of miRNAs.

Ludwig Nicole N Kim Yoo-Jin YJ Mueller Sabine C SC Backes Christina C Werner Tamara V TV Galata Valentina V Sartorius Elke E Bohle Rainer M RM Keller Andreas A Meese Eckart E

Neuro-oncology 20150213 9

<h4>Background</h4>Micro (mi)RNAs are key regulators of gene expression and offer themselves as biomarkers for cancer development and progression. Meningioma is one of the most frequent primary intracranial tumors. As of yet, there are limited data on the role of miRNAs in meningioma of different histological subtypes and the affected signaling pathways.<h4>Methods</h4>In this study, we compared expression of 1205 miRNAs in different meningioma grades and histological subtypes using microarrays ...[more]

PMID: 25681310

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Project description:Exosomes are small-diameter endosomal vesicles secreted in all biological fluids and play biological/pathological roles in the cell. These pathological roles are played by exosome's cargo molecules through inter-cellular communication. Exosomal cargo molecules contain proteins and miRNAs. miRNAs are small non-coding RNA fragments involved in the reduction of final protein output by destabilizing or suppressing the translation of target messenger RNA (mRNA). This deregulation of the protein due to miRNAs ultimately accelerates the process of disease pathogenesis. The role of exosomal miRNAs has been investigated in different diseases and the limited number of studies have been published concerning exosomal miRNAs and rheumatoid arthritis (RA). The current study is designed to investigate the role of exosomal miRNAs (miRNA-103a-3p, miRNA-10a-5p, miRNA-204-3p, miRNA-330-3p, and miRNA-19b) in the pathogenesis of RA. Furthermore, the role of selected exosomal miRNAs in RA pathogenesis was further explored by estimating oxidative stress and histone deacetylation in RA patients. In the current study, 306 RA patients and equal numbers of age/gender-matched controls were used. The level of expression of above-mentioned exosomal miRNAs was assessed by performing qRT PCR. Deacetylation and oxidative stress assays were performed to estimate the 8-hydroxydeoxyguanosine (8-OHdG level) and histone deacetylation levels using the Enzyme-linked immunosorbent assay (ELISA). Statistical analysis indicated a significantly downregulated expression of miRNA-103a-3p (p<0.0001), miR-10a-5p (p<0.0001), miR-204-3p (p<0.0001), miR-330-3p (p<0.0001) and miR-19b (p<0.0001) in RA patients compared to controls. Significantly increased levels of 8-OHdG (p<0.0001) and histone deacetylation (p<0.0001) were observed among RA patients compared to controls. Spearman correlation showed a negative correlation between the deregulated exosomal miRNAs and increased oxidative stress and histone deacetylation in RA patients. Receiver operating characteristics (ROC) curve analysis showed a good diagnostic specificity/sensitivity of the above-mentioned exosomal miRNAs among RA patients. These analyses indicated the potential role of deregulated exosomal miRNAs in the initiation of RA by targeting oxidative stress and histone deacetylation processes.

Project description:BackgroundEnterovirus 71 (EV71) is one of the major etiological pathogens of hand, foot and mouth disease (HFMD) and can cause severe cerebral and pulmonary complications and even fatality. MicroRNAs (miRNAs), a class of small non-coding RNA molecules, play an important role in post-transcriptional regulation of gene expression and thereby influencing various physiological and pathological processes. Increasing evidence suggests that miRNAs act as key effector molecules in the complicated pathogen-host interactions. However, the roles of miRNAs in EV71 infection and pathogenesis are not well understood.MethodsTo identify special miRNAs involved in EV71 infection, a microarray assay was performed to study the expression pattern of miRNAs in EV71-infected human rhabdomyosarcoma cells (RD cells) and uninfected RD cells. We further predicted the putative target genes for the dysregulated miRNAs using the online bioinformatic algorithms (TargetScan, miRanda and PicTar) and carried out functional annotation including GO enrichment and KEGG pathway analysis for miRNA predicted targets. Then, the results of microarray were further confirmed by quantitative RT-PCR.ResultsTotally, 45 differentially expressed miRNAs ware identified by microarray, among which 36 miRNAs were up-regulated and 9 were down-regulated. 7166 predicted target genes for the dysregulated miRNAs were revealed by using TargetScan in conjunction with miRanda and PicTar. The GO annotation suggested that predicted targets of miRNAs were enriched into the category of signal transduction, regulation of transcription, metabolic process, protein phosphorylation, apoptotic process and immune response. KEGG pathway analysis suggested that these predicted target genes were involved in many important pathways, mainly including endocytosis and focal adhesion, MAPK signaling pathway, hypertrophic cardiomyopathy, melanogenesis and ErbB signaling pathway. The expression levels of 8 most differentially up-regulated miRNAs and 3 most differentially down-regulated miRNAs were confirmed by qRT-PCR. The expressions of hsa-miR-4530, hsa-miR-4492, hsa-miR-6125, hsa-miR-494-3p, hsa-miR-638, hsa-miR-6743-5p, hsa-miR-4459 and hsa-miR-4443 detected by qRT-PCR were consistent with the microarray data.ConclusionThese results might extend our understanding to the regulatory mechanism of miRNAs underlying the pathogenesis of EV71 infection, thus strengthening the preventative and therapeutic strategies of HFMD caused by EV71.

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Posttranscriptional deregulation of signaling pathways in meningioma subtypes by differential expression of miRNAs.

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Posttranscriptional deregulation of signaling pathways in meningioma subtypes by differential expression of miRNAs.

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