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dc.contributor.author Hjelmeland, AB
dc.contributor.author Wu, Q
dc.contributor.author Wickman, S
dc.contributor.author Eyler, C
dc.contributor.author Heddleston, J
dc.contributor.author Shi, Q
dc.contributor.author Lathia, JD
dc.contributor.author Macswords, J
dc.contributor.author Lee, J
dc.contributor.author McLendon, RE
dc.contributor.author Rich, JN
dc.coverage.spatial United States
dc.date.accessioned 2011-06-21T17:31:05Z
dc.date.issued 2010-02-23
dc.identifier http://www.ncbi.nlm.nih.gov/pubmed/20186265
dc.identifier.citation PLoS Biol, 2010, 8 (2), pp. e1000319 - ?
dc.identifier.uri http://hdl.handle.net/10161/4444
dc.description.abstract Glioblastomas are deadly cancers that display a functional cellular hierarchy maintained by self-renewing glioblastoma stem cells (GSCs). GSCs are regulated by molecular pathways distinct from the bulk tumor that may be useful therapeutic targets. We determined that A20 (TNFAIP3), a regulator of cell survival and the NF-kappaB pathway, is overexpressed in GSCs relative to non-stem glioblastoma cells at both the mRNA and protein levels. To determine the functional significance of A20 in GSCs, we targeted A20 expression with lentiviral-mediated delivery of short hairpin RNA (shRNA). Inhibiting A20 expression decreased GSC growth and survival through mechanisms associated with decreased cell-cycle progression and decreased phosphorylation of p65/RelA. Elevated levels of A20 in GSCs contributed to apoptotic resistance: GSCs were less susceptible to TNFalpha-induced cell death than matched non-stem glioma cells, but A20 knockdown sensitized GSCs to TNFalpha-mediated apoptosis. The decreased survival of GSCs upon A20 knockdown contributed to the reduced ability of these cells to self-renew in primary and secondary neurosphere formation assays. The tumorigenic potential of GSCs was decreased with A20 targeting, resulting in increased survival of mice bearing human glioma xenografts. In silico analysis of a glioma patient genomic database indicates that A20 overexpression and amplification is inversely correlated with survival. Together these data indicate that A20 contributes to glioma maintenance through effects on the glioma stem cell subpopulation. Although inactivating mutations in A20 in lymphoma suggest A20 can act as a tumor suppressor, similar point mutations have not been identified through glioma genomic sequencing: in fact, our data suggest A20 may function as a tumor enhancer in glioma through promotion of GSC survival. A20 anticancer therapies should therefore be viewed with caution as effects will likely differ depending on the tumor type.
dc.format.extent e1000319 - ?
dc.language eng
dc.language.iso en_US en_US
dc.relation.ispartof PLoS Biol
dc.relation.isversionof 10.1371/journal.pbio.1000319
dc.subject Animals
dc.subject Blotting, Western
dc.subject Cell Survival
dc.subject Cells, Cultured
dc.subject DNA-Binding Proteins
dc.subject Flow Cytometry
dc.subject Fluorescent Antibody Technique
dc.subject Gene Expression Regulation, Neoplastic
dc.subject Glioblastoma
dc.subject Humans
dc.subject In Situ Nick-End Labeling
dc.subject Intracellular Signaling Peptides and Proteins
dc.subject Mice
dc.subject Mice, Nude
dc.subject Mutation
dc.subject Neoplastic Stem Cells
dc.subject Nuclear Proteins
dc.subject Polymerase Chain Reaction
dc.subject Survival Analysis
dc.subject Transplantation, Heterologous
dc.title Targeting A20 decreases glioma stem cell survival and tumor growth.
dc.title.alternative en_US
dc.type Journal Article
dc.description.version Version of Record en_US
duke.date.pubdate 2010-2-0 en_US
duke.description.endpage e1000319 en_US
duke.description.issue 2 en_US
duke.description.startpage e1000319 en_US
duke.description.volume 8 en_US
dc.relation.journal Plos Biology en_US
pubs.author-url http://www.ncbi.nlm.nih.gov/pubmed/20186265
pubs.issue 2
pubs.organisational-group /Duke
pubs.organisational-group /Duke/School of Medicine
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments/Pathology
pubs.organisational-group /Duke/School of Medicine/Institutes and Centers
pubs.organisational-group /Duke/School of Medicine/Institutes and Centers/Duke Cancer Institute
pubs.publication-status Published online
pubs.volume 8
dc.identifier.eissn 1545-7885

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