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Gene expression of growth signaling pathways is up-regulated in CD133-positive medulloblastoma cells.

ABSTRACT: Medulloblastoma (MB) is the most common malignant brain tumor in children. Cancer initiating cells (CICs) have been proposed to be involved in the development of brain tumors including MB. Prominin-1 antigen (CD133) is a candidate surface molecular marker for CICs. In the present study, CD133-positive cells were isolated from human Daoy MB cells and their gene expression was compared with that of control Daoy cells. DNA microarray analysis revealed that there were 398 up-regulated genes (>2-fold increase) and 318 down-regulated genes (<50% decrease) in the CD133-positive cell-enriched fractions. Up-regulated genes included neuregulin-1, cyclin D1, cyclin-dependent kinase 6, vascular endothelial growth factor, inhibin ? A, promyelocytic leukemia gene, MYC, and hairy enhancer of split-1, which are components of growth signaling pathways. Molecular studies suggest that developmentally regulated signals important for stem cell maintenance are also involved in MB tumorigenesis. Moreover, these molecules can serve as novel targets for MB treatment.

SUBMITTER: Gu C

PROVIDER: S-EPMC3410605 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Gene expression of growth signaling pathways is up-regulated in CD133-positive medulloblastoma cells.

Gu Chunyu C Yokota Naoki N Gao Yun Y Yamamoto Junkoh J Tokuyama Tsutomu T Namba Hiroki H

Oncology letters 20110114 2

Medulloblastoma (MB) is the most common malignant brain tumor in children. Cancer initiating cells (CICs) have been proposed to be involved in the development of brain tumors including MB. Prominin-1 antigen (CD133) is a candidate surface molecular marker for CICs. In the present study, CD133-positive cells were isolated from human Daoy MB cells and their gene expression was compared with that of control Daoy cells. DNA microarray analysis revealed that there were 398 up-regulated genes (>2-fold ...[more]

PMID: 22866088

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Project description:MEK1, a member of the mitogen-activated protein kinase (MAPK) cascade that directly activates extracellular signal-regulated kinase (ERK), induces cardiac hypertrophy in transgenic mice. Calcineurin is a calcium-regulated protein phosphatase that also functions as a positive regulator of cardiac hypertrophic growth through a direct mechanism involving activation of nuclear factor of activated T-cell (NFAT) transcription factors. Here we determined that calcineurin-NFAT and MEK1-ERK1/2 signaling pathways are interdependent in cardiomyocytes, where they directly coregulate the hypertrophic growth response. For example, genetic deletion of the calcineurin Abeta gene reduced the hypertrophic response elicited by an activated MEK1 transgene in the heart, while inhibition of calcineurin or NFAT in cultured neonatal cardiomyocytes also blunted the hypertrophic response driven by activated MEK1. Conversely, targeted inhibition of MEK1-ERK1/2 signaling in cultured cardiomyocytes attenuated the hypertrophic growth response directed by activated calcineurin. However, targeted inhibition of MEK1-ERK1/2 signaling did not directly affect calcineurin-NFAT activation, nor was MEK1-ERK1/2 activation altered by targeted inhibition of calcineurin-NFAT. Mechanistically, we show that MEK1-ERK1/2 signaling augments NFAT transcriptional activity independent of calcineurin, independent of changes in NFAT nuclear localization, and independent of alterations in NFAT transactivation potential. In contrast, MEK1-ERK1/2 signaling enhances NFAT-dependent gene expression through an indirect mechanism involving induction of cardiac AP-1 activity, which functions as a necessary NFAT-interacting partner. As a second mechanism, MEK1-ERK1/2 and calcineurin-NFAT proteins form a complex in cardiac myocytes, resulting in direct phosphorylation of NFATc3 within its C terminus. MEK1-ERK1/2-mediated phosphorylation of NFATc3 directly augmented its DNA binding activity, while inhibition of MEK1-ERK1/2 signaling reduced NFATc3 DNA binding activity. Collectively, these results indicate that calcineurin-NFAT and MEK1-ERK1/2 pathways constitute a codependent signaling module in cardiomyocytes that coordinately regulates the growth response through two distinct mechanisms.

Project description:BackgroundUsing a pathway-focused approach, we aimed to provide a subgroup-specific basis for finding novel therapeutic strategies and further refinement of the risk stratification in pediatric medulloblastoma.MethodBased on genome-wide Cox regression and Gene Set Enrichment Analysis, we investigated prognosis-related signaling pathways and core genes in pediatric medulloblastoma subgroups using 530 patient data from Medulloblastoma Advanced Genomic International Consortium (MAGIC) project. We further examined the relationship between expression of the prognostic core genes and frequent chromosome aberrations using broad range copy number change data.ResultsIn SHH subgroup, relatively high expression of the core genes involved in p53, PLK1, FOXM1, and Aurora B signaling pathways are associated with poor prognosis, and their average expression synergistically increases with co-occurrence of losses of 17p, 14q, or 10q, or gain of 17q. In Group 3, in addition to high MYC expression, relatively elevated expression of PDGFRA, IGF1R, and FGF2 and their downstream genes in PI3K/AKT and MAPK/ERK pathways are related to poor survival outcome, and their average expression is increased with the presence of isochromosome 17q [i(17q)] and synergistically down-regulated with simultaneous losses of 16p, 8q, or 4q. In Group 4, up-regulation of the genes encoding various immune receptors and those involved in NOTCH, NF-κB, PI3K/AKT, or RHOA signaling pathways are associated with worse prognosis. Additionally, the expressions of Notch genes correlate with those of the prognostic immune receptors. Besides the Group 4 patients with previously known prognostic aberration, loss of chromosome 11, those with loss of 8q but without i(17q) show excellent survival outcomes and low average expression of the prognostic core genes whereas those harboring 10q loss, 1q gain, or 12q gain accompanied by i(17q) show bad outcomes. Finally, several metabolic pathways known to be reprogrammed in cancer cells are detected as prognostic pathways including glutamate metabolism in SHH subgroup, pentose phosphate pathway and TCA cycle in Group 3, and folate-mediated one carbon-metabolism in Group 4.ConclusionsThe results underscore several subgroup-specific pathways for potential therapeutic interventions: SHH-GLI-FOXM1 pathway in SHH subgroup, receptor tyrosine kinases and their downstream pathways in Group 3, and immune and inflammatory pathways in Group 4.

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Gene expression of growth signaling pathways is up-regulated in CD133-positive medulloblastoma cells.

Publications

Gene expression of growth signaling pathways is up-regulated in CD133-positive medulloblastoma cells.

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