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MicroRNA and target protein patterns reveal physiopathological features of glioma subtypes.

Lages E, Guttin A, El Atifi M, Ramus C, Ipas H, Dupré I, Rolland D, Salon C, Godfraind C, deFraipont F, Dhobb M, Pelletier L, Wion D, Gay E, Berger F, Issartel JP - PLoS ONE (2011)

Bottom Line: Another aim of this study was to better understand glioma physiopathology looking for targets of deregulated microRNAs.We discovered that some targets of these microRNAs such as STAT3, PTBP1 or SIRT1 are differentially expressed in gliomas consistent with deregulation of microRNA expression.Understanding the connections between microRNAs and bioenergetic pathways in gliomas may lead to identification of novel therapeutic targets.

View Article: PubMed Central - PubMed

Affiliation: Team7 Nanomedicine and Brain, INSERM U836, Grenoble, France.

ABSTRACT
Gliomas such as oligodendrogliomas (ODG) and glioblastomas (GBM) are brain tumours with different clinical outcomes. Histology-based classification of these tumour types is often difficult. Therefore the first aim of this study was to gain microRNA data that can be used as reliable signatures of oligodendrogliomas and glioblastomas. We investigated the levels of 282 microRNAs using membrane-array hybridisation and real-time PCR in ODG, GBM and control brain tissues. In comparison to these control tissues, 26 deregulated microRNAs were identified in tumours and the tissue levels of seven microRNAs (miR-21, miR-128, miR-132, miR-134, miR-155, miR-210 and miR-409-5p) appropriately discriminated oligodendrogliomas from glioblastomas. Genomic, epigenomic and host gene expression studies were conducted to investigate the mechanisms involved in these deregulations. Another aim of this study was to better understand glioma physiopathology looking for targets of deregulated microRNAs. We discovered that some targets of these microRNAs such as STAT3, PTBP1 or SIRT1 are differentially expressed in gliomas consistent with deregulation of microRNA expression. Moreover, MDH1, the target of several deregulated microRNAs, is repressed in glioblastomas, making an intramitochondrial-NAD reduction mediated by the mitochondrial aspartate-malate shuttle unlikely. Understanding the connections between microRNAs and bioenergetic pathways in gliomas may lead to identification of novel therapeutic targets.

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Methylation levels of CpG islands located upstream of the transcriptional starts of miRNA coding regions.Promoter regions of seven different miRNA genes were analyzed for the presence of CpG islands and for their methylation level. DNA fragments amplified from CpG islands were analyzed by pyrosequencing as described in Materials and Methods. Two different CpG islands were investigated for miR-339 coding region upstream transcription start sites, TSS1 and TSS2. Methylation levels are reported as ratios between gliomas (GBM or ODG) versus control brain tissue (left y-axis). Black bars: GBM/N ratios; white bars: ODG/N ratios. GBM to ODG miRNA expression levels are reported in open triangles (right y-axis).
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pone-0020600-g002: Methylation levels of CpG islands located upstream of the transcriptional starts of miRNA coding regions.Promoter regions of seven different miRNA genes were analyzed for the presence of CpG islands and for their methylation level. DNA fragments amplified from CpG islands were analyzed by pyrosequencing as described in Materials and Methods. Two different CpG islands were investigated for miR-339 coding region upstream transcription start sites, TSS1 and TSS2. Methylation levels are reported as ratios between gliomas (GBM or ODG) versus control brain tissue (left y-axis). Black bars: GBM/N ratios; white bars: ODG/N ratios. GBM to ODG miRNA expression levels are reported in open triangles (right y-axis).

Mentions: Expression levels of miRNAs can also be controlled by epigenetic changes such as methylations of CpG islands in promoters. We screened the genomic sequences for the presence of CpG islands in the 2-kbp region upstream of the transcription start sites and analysed by pyrosequencing eight CpG islands upstream of the genes that encode seven different miRNAs (Fig. 2).


MicroRNA and target protein patterns reveal physiopathological features of glioma subtypes.

Lages E, Guttin A, El Atifi M, Ramus C, Ipas H, Dupré I, Rolland D, Salon C, Godfraind C, deFraipont F, Dhobb M, Pelletier L, Wion D, Gay E, Berger F, Issartel JP - PLoS ONE (2011)

Methylation levels of CpG islands located upstream of the transcriptional starts of miRNA coding regions.Promoter regions of seven different miRNA genes were analyzed for the presence of CpG islands and for their methylation level. DNA fragments amplified from CpG islands were analyzed by pyrosequencing as described in Materials and Methods. Two different CpG islands were investigated for miR-339 coding region upstream transcription start sites, TSS1 and TSS2. Methylation levels are reported as ratios between gliomas (GBM or ODG) versus control brain tissue (left y-axis). Black bars: GBM/N ratios; white bars: ODG/N ratios. GBM to ODG miRNA expression levels are reported in open triangles (right y-axis).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3105101&req=5

pone-0020600-g002: Methylation levels of CpG islands located upstream of the transcriptional starts of miRNA coding regions.Promoter regions of seven different miRNA genes were analyzed for the presence of CpG islands and for their methylation level. DNA fragments amplified from CpG islands were analyzed by pyrosequencing as described in Materials and Methods. Two different CpG islands were investigated for miR-339 coding region upstream transcription start sites, TSS1 and TSS2. Methylation levels are reported as ratios between gliomas (GBM or ODG) versus control brain tissue (left y-axis). Black bars: GBM/N ratios; white bars: ODG/N ratios. GBM to ODG miRNA expression levels are reported in open triangles (right y-axis).
Mentions: Expression levels of miRNAs can also be controlled by epigenetic changes such as methylations of CpG islands in promoters. We screened the genomic sequences for the presence of CpG islands in the 2-kbp region upstream of the transcription start sites and analysed by pyrosequencing eight CpG islands upstream of the genes that encode seven different miRNAs (Fig. 2).

Bottom Line: Another aim of this study was to better understand glioma physiopathology looking for targets of deregulated microRNAs.We discovered that some targets of these microRNAs such as STAT3, PTBP1 or SIRT1 are differentially expressed in gliomas consistent with deregulation of microRNA expression.Understanding the connections between microRNAs and bioenergetic pathways in gliomas may lead to identification of novel therapeutic targets.

View Article: PubMed Central - PubMed

Affiliation: Team7 Nanomedicine and Brain, INSERM U836, Grenoble, France.

ABSTRACT
Gliomas such as oligodendrogliomas (ODG) and glioblastomas (GBM) are brain tumours with different clinical outcomes. Histology-based classification of these tumour types is often difficult. Therefore the first aim of this study was to gain microRNA data that can be used as reliable signatures of oligodendrogliomas and glioblastomas. We investigated the levels of 282 microRNAs using membrane-array hybridisation and real-time PCR in ODG, GBM and control brain tissues. In comparison to these control tissues, 26 deregulated microRNAs were identified in tumours and the tissue levels of seven microRNAs (miR-21, miR-128, miR-132, miR-134, miR-155, miR-210 and miR-409-5p) appropriately discriminated oligodendrogliomas from glioblastomas. Genomic, epigenomic and host gene expression studies were conducted to investigate the mechanisms involved in these deregulations. Another aim of this study was to better understand glioma physiopathology looking for targets of deregulated microRNAs. We discovered that some targets of these microRNAs such as STAT3, PTBP1 or SIRT1 are differentially expressed in gliomas consistent with deregulation of microRNA expression. Moreover, MDH1, the target of several deregulated microRNAs, is repressed in glioblastomas, making an intramitochondrial-NAD reduction mediated by the mitochondrial aspartate-malate shuttle unlikely. Understanding the connections between microRNAs and bioenergetic pathways in gliomas may lead to identification of novel therapeutic targets.

Show MeSH
Related in: MedlinePlus