Journal
CELLULAR SIGNALLING
Volume 24, Issue 2, Pages 549-559Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2011.10.008
Keywords
CD44; MMP-9; Invasion; Glioblastoma; Xenograft cells
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Funding
- National Institute of Neurological Disorders and Stroke (NINDS) [NS047699]
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CD44 is implicated in cell-cell and cell-matrix adhesion, cell migration, and signaling. CD44 cleavage correlates with the tumor burden and metastatic potential in various cancers. In this study, we demonstrate that matrix metalloproteinase-9 (MMP-9) acts as a processing enzyme for CD44 cleavage. Further, this processing event stimulates cell motility and inhibition of either CD44 or MMP-9 inhibited cell migration. MMP-9 and CD44 co-localization on the cell surface was observed in the histological sections of human glioblastoma (GBM) tissues. Confocal microscopy and co-immunoprecipitation studies in GEM xenograft cells further confirm this interaction. The interaction of MMP-9 with CD44 induced CD44 cleavage which was inhibited by both transcriptional knockdown of MMP-9 and with MMP-9 specific inhibitor. Further, supplementation of purified and activated human MMP-9 (hMMP-9) in MMP-9-knockdown cells resumed CD44 cleavage and migration. Additionally, activated hMMP-9 protein induced cleavage of recombinant human CD44 (rhCD44) in an in vitro assay. Selective overexpression of either extracellular domain (CD44(ECD)) or intracellular domain (CD44(ICD)) confirmed that CD44(ECD)) played a role in cell migration and invasion. Taken together, our results suggest that MMP-9 is involved in the shedding of CD44 from cancer cells, which would promote the malignant potential of tumor cells. (C) 2011 Elsevier Inc. All rights reserved.
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