Abstract
Matrix metalloproteinase 9 (MMP-9) is known to play a major role in cell migration and invasion in both physiological and pathological processes. Our previous work has shown that increased MMP-9 levels are associated with human glioma tumor progression. In this study, we evaluated the ability of an adenovirus containing a 528 bp cDNA sequence in antisense orientation to the 5′ end of the human MMP-9 gene (Ad-MMP-9AS) to inhibit the invasiveness and migratory capacity of the human glioblastoma cell line SBN19 in in vitro and in vivo models. Infection of glioma cells with Ad-MMP-9AS reduced MMP-9 enzyme activity by approximately 90% compared with mock- or Ad-CMV-infected cells. Migration and invasion of glioblastoma cells infected with Ad-MMP-9AS were significantly inhibited relative to Ad-CMV-infected controls in spheroid and Matrigel assays. Intracranial injections of SNB19 cells infected with Ad-MMP-9AS did not produce tumors in nude mice. However, injecting the Ad-MMP-9AS construct into subcutaneous U87MG tumors in nude mice caused regression of tumor growth. These results support the theory that adenoviral-mediated delivery of the MMP-9 gene in the antisense orientation has therapeutic potential for treating gliomas.
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Abbreviations
- ECM:
-
extracellular matrix
- MMP:
-
matrix metalloproteinase
- MT-MMP:
-
membrane-type MMP
- Ad:
-
adenovirus
- CMV:
-
cytomegalovirus
- MOI:
-
multiplicities of infection
- PFU:
-
plaque-forming units
- PMA:
-
phorbol myristate acetate
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Acknowledgements
We thank Karen Minter for preparing the manuscript and Christine Wogan for editorial review. Supported by NIH grants (CA76350 and CA75557; Jasti S Rao).
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Lakka, S., Rajan, M., Gondi, C. et al. Adenovirus-mediated expression of antisense MMP-9 in glioma cells inhibits tumor growth and invasion. Oncogene 21, 8011–8019 (2002). https://doi.org/10.1038/sj.onc.1205894
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DOI: https://doi.org/10.1038/sj.onc.1205894
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