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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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Metabolic pathways and enzymatic roles of MDH1, IDH1 and SIRT1.ACSS2: acyl-CoA synthetase short-chain family member 2; IDH1: isocitrate dehydrogenase 1 (NADP+), soluble1; GOT1: glutamic-oxaloacetic transaminase 1; GOT2: glutamic-oxaloacetic transaminase 2; MDH1: malate dehydrogenase 1, NAD (soluble); MDH2: malate dehydrogenase 2, NAD (mitochondrial); SIRT1: sirtuin 1. Inactivating mutations in IDH1 have been reported to be frequent in oligodendrogliomas [8].
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pone-0020600-g004: Metabolic pathways and enzymatic roles of MDH1, IDH1 and SIRT1.ACSS2: acyl-CoA synthetase short-chain family member 2; IDH1: isocitrate dehydrogenase 1 (NADP+), soluble1; GOT1: glutamic-oxaloacetic transaminase 1; GOT2: glutamic-oxaloacetic transaminase 2; MDH1: malate dehydrogenase 1, NAD (soluble); MDH2: malate dehydrogenase 2, NAD (mitochondrial); SIRT1: sirtuin 1. Inactivating mutations in IDH1 have been reported to be frequent in oligodendrogliomas [8].

Mentions: In the cytosol, SIRT1 also deacetylates and activates acetyl-CoA synthetase (ACSS2) in the presence of oxidised NAD (Fig. 4). As a consequence of the absence of SIRT1 in gliomas, ACSS2-dependent production of acetyl-CoA from acetate will be aborted. Acetyl-CoA, an important metabolite for cell energy and a precursor at the cross-roads of several metabolic pathways, can also be produced, at least in adipose tissue, as an end-product of a pathway that starts by transamination between pyruvate and glutamate [56] (Fig. 4). In this pathway, IDH1, the cytosolic form of isocitrate dehydrogenase, produces isocitrate from alpha-ketoglutarate. In addition, oxaloacetate – a substrate of MDH1 – is co-produced with acetyl-CoA. If this glutamate-dependent acetyl-CoA generation pathway functions in glial cells, in gliomas the mutations of IDH1 or the low amounts of MDH1 are expected to reduce the concomitant production of acetyl-CoA and oxaloacetate through this pathway.


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)

Metabolic pathways and enzymatic roles of MDH1, IDH1 and SIRT1.ACSS2: acyl-CoA synthetase short-chain family member 2; IDH1: isocitrate dehydrogenase 1 (NADP+), soluble1; GOT1: glutamic-oxaloacetic transaminase 1; GOT2: glutamic-oxaloacetic transaminase 2; MDH1: malate dehydrogenase 1, NAD (soluble); MDH2: malate dehydrogenase 2, NAD (mitochondrial); SIRT1: sirtuin 1. Inactivating mutations in IDH1 have been reported to be frequent in oligodendrogliomas [8].
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3105101&req=5

pone-0020600-g004: Metabolic pathways and enzymatic roles of MDH1, IDH1 and SIRT1.ACSS2: acyl-CoA synthetase short-chain family member 2; IDH1: isocitrate dehydrogenase 1 (NADP+), soluble1; GOT1: glutamic-oxaloacetic transaminase 1; GOT2: glutamic-oxaloacetic transaminase 2; MDH1: malate dehydrogenase 1, NAD (soluble); MDH2: malate dehydrogenase 2, NAD (mitochondrial); SIRT1: sirtuin 1. Inactivating mutations in IDH1 have been reported to be frequent in oligodendrogliomas [8].
Mentions: In the cytosol, SIRT1 also deacetylates and activates acetyl-CoA synthetase (ACSS2) in the presence of oxidised NAD (Fig. 4). As a consequence of the absence of SIRT1 in gliomas, ACSS2-dependent production of acetyl-CoA from acetate will be aborted. Acetyl-CoA, an important metabolite for cell energy and a precursor at the cross-roads of several metabolic pathways, can also be produced, at least in adipose tissue, as an end-product of a pathway that starts by transamination between pyruvate and glutamate [56] (Fig. 4). In this pathway, IDH1, the cytosolic form of isocitrate dehydrogenase, produces isocitrate from alpha-ketoglutarate. In addition, oxaloacetate – a substrate of MDH1 – is co-produced with acetyl-CoA. If this glutamate-dependent acetyl-CoA generation pathway functions in glial cells, in gliomas the mutations of IDH1 or the low amounts of MDH1 are expected to reduce the concomitant production of acetyl-CoA and oxaloacetate through this pathway.

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