Abstract
Pilocytic astrocytoma (PA) is the most common primary brain tumor in children; various signaling pathways have been implicated in its biology. The Notch signaling pathway has been found to play a role in the development, stem cell biology, and pathogenesis of several cancers, but its role in PA has not been investigated. We studied alterations in Notch signaling components in tumor tissue from 18 patients with PA and 4 with other low-grade astrocytomas to identify much needed therapeutic targets. We found that Notch pathway members were overexpressed at the mRNA (NOTCH1, NOTCH2, HEY1, HEY2) and protein (HES1) levels in PAs at various anatomic sites compared with non-neoplastic brain samples. These changes were not associated with specific BRAF alterations. Inhibiting the Notch pathway in the pediatric low-grade astrocytoma cell lines Res186 and Res259 using either RNA interference or a γ-secretase inhibitor resulted in variable, but significant, reduction in cell growth and migration. This study suggests a potential role for Notch signaling in pediatric low-grade astrocytoma tumorigenesis and that Notch signaling may be a viable pathway therapeutic target.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adolescent
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Antineoplastic Agents / pharmacology
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Astrocytoma / genetics
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Astrocytoma / metabolism*
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Astrocytoma / pathology
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / metabolism
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Brain Neoplasms / metabolism*
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Brain Neoplasms / pathology
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Cell Line, Tumor
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Cell Movement / drug effects
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Cell Proliferation / drug effects
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Cell Proliferation / genetics
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Child
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Child, Preschool
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Core Binding Factors / genetics
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Core Binding Factors / metabolism
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Cyclic S-Oxides / pharmacology
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Enzyme Inhibitors / pharmacology
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Female
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Gene Expression Regulation, Neoplastic / drug effects
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Gene Expression Regulation, Neoplastic / physiology*
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism
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Humans
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Immunoglobulin J Recombination Signal Sequence-Binding Protein / genetics
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Male
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Receptors, Notch / genetics
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Receptors, Notch / metabolism*
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Signal Transduction / drug effects
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Signal Transduction / physiology*
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Thiadiazoles / pharmacology
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Transcription Factor HES-1
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Young Adult
Substances
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Antineoplastic Agents
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Basic Helix-Loop-Helix Transcription Factors
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Core Binding Factors
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Cyclic S-Oxides
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Enzyme Inhibitors
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Homeodomain Proteins
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Immunoglobulin J Recombination Signal Sequence-Binding Protein
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MRK 003
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RBPJ protein, human
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Receptors, Notch
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Thiadiazoles
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Transcription Factor HES-1
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HES1 protein, human