Abstract | BACKGROUND: METHODS: Transwell inserts coated with extracellular matrix proteins were used to determine the role of TNC in BTIC invasion. Microarray analysis, lentiviral constructs, RNA interference-mediated knockdown, and activity assay ascertained the role of proteases in TNC-stimulated BTIC invasion in culture. Involvement of proteases was validated using orthotopic brain xenografts in mice. RESULTS: TNC stimulated BTIC invasiveness in a metalloproteinase-dependent manner. A global gene expression screen identified the metalloproteinase ADAM-9 as a potential regulator of TNC-stimulated BTIC invasiveness, and this was corroborated by an increase of ADAM-9 protein in 4 glioma patient-derived BTIC lines. Notably, RNA interference to ADAM-9, as well as inhibition of mitogen-activated protein kinase 8 (c-Jun NH2-terminal kinase), attenuated TNC-stimulated ADAM-9 expression, proteolytic activity, and BTIC invasiveness. The relevance of ADAM-9 to tumor invasiveness was validated using resected human glioblastoma specimens and orthotopic xenografts where elevation of ADAM-9 and TNC expression was prominent at the invasive front of the tumor. CONCLUSIONS: This study has identified TNC as a promoter of the invasiveness of BTICs through a mechanism involving ADAM-9 proteolysis via the c-Jun NH2-terminal kinase pathway.
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Authors | Susobhan Sarkar, Franz J Zemp, Donna Senger, Stephen M Robbins, V Wee Yong |
Journal | Neuro-oncology
(Neuro Oncol)
Vol. 17
Issue 8
Pg. 1095-105
(Aug 2015)
ISSN: 1523-5866 [Electronic] England |
PMID | 25646025
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: [email protected]. |
Chemical References |
- Membrane Proteins
- Tenascin
- ADAM Proteins
- ADAM9 protein, human
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Topics |
- ADAM Proteins
(metabolism)
- Animals
- Brain Neoplasms
(metabolism, pathology)
- Cell Line, Tumor
- Glioblastoma
(metabolism, pathology)
- Humans
- MAP Kinase Signaling System
- Membrane Proteins
(metabolism)
- Mice
- Neoplasm Invasiveness
- Neoplastic Stem Cells
(metabolism, pathology)
- Tenascin
(pharmacology, physiology)
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