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Adenovirus-mediated expression of antisense MMP-9 in glioma cells inhibits tumor growth and invasion

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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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Authors and Affiliations

  1. Division of Cancer Biology, Department of Biomedical and Therapeutic Sciences, University of Illinois, Peoria, Illinois, USA

    Sajani S Lakka, Christopher Gondi, Niranjan Yanamandra, Nirmala Chandrasekar, Khawar Siddique & Jasti S Rao

  2. Department of Neurosurgery, University of Illinois, Peoria, Illinois, USA

    William Olivero, Dzung H Dinh & Jasti S Rao

  3. Department of Neuro-pathology, University of Illinois, Peoria, Illinois, USA

    Meena Gujrati

  4. Department of Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA

    Mannari Rajan

  5. Department of Neuro-Oncology, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA

    Sushma L Jasti

  6. Department of Neurological Surgery, Okayama University Medical School, Okayama, Japan

    Yoshiaki Adachi

  7. Department of Propedeutic Surgery, Athens University School of Medicine, Athens, Greece

    Gregory Kouraklis

  8. Department of Neurology, University of Ioannina School of Medicine, Ioannina, Greece

    Athanassios P Kyritsis

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  1. Sajani S Lakka
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  2. Mannari Rajan
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  11. Dzung H Dinh
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  12. Gregory Kouraklis
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  14. Jasti S Rao
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Correspondence to 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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