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Adenovirus-mediated transfer of siRNA against MMP-2 mRNA results in impaired invasion and tumor-induced angiogenesis, induces apoptosis in vitro and inhibits tumor growth in vivo in glioblastoma

Oncogene volume 27, pages 4830–4840 (2008)Cite this article

Abstract

Invasive tumors, including gliomas, utilize proteinases to degrade extracellular matrix components and diffuse into the adjacent tissues or migrate toward distant ones. In addition, proteinase activity is required for the formation of new blood vessels within the tumor. Levels of the proteinase matrix metalloproteinase-2 (MMP-2) are highly increased in gliomas. In this study, we examined the effect of the downregulation of MMP-2 via adenovirus-mediated siRNA in gliomas. Here, we show that siRNA delivery significantly decreased levels of MMP-2 in the glioblastoma cell lines U-87 and U-251. U-87 and U-251 cells showed impaired invasion through matrigel as well as decreased migration from tumor spheroids transfected with adenoviral vector expressing siRNA against MMP-2. Additionally, tumor-induced angiogenesis was decreased in in vitro experiments in cultured human microvascular endothelial cells (HMECs) in serum-free conditioned medium of glioblastoma cells transfected with these constructs and co-cultures of glioma cells with HMECs. We also observed decreased angiogenesis in the in vivo dorsal skin-fold chamber model. Moreover, MMP-2 inhibition induced apoptotic cell death in vitro, and suppressed tumor growth of preestablished U-251 intracranial xenografts in nude mice. Thus, specific targeting of MMP-2 may provide a novel, efficient approach for the treatment of gliomas and improve the poor outcomes of patients with these brain tumors.

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Acknowledgements

We thank Shellee Abraham for preparing the article and Diana Meister and Sushma Jasti for the review. We also thank Noorjehan Ali for technical assistance. This research was supported by National Cancer Institute grants CA 75557, CA 92393, CA 95058, CA 116708, NINDS NS 47699, NS57529, NS61835, and Caterpillar Inc., OSF St Francis Inc., Peoria, IL (to JSR).

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Author notes

  1. O Kargiotis and C Chetty: These two authors contributed equally to this work.

Authors and Affiliations

  1. Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, IL, USA

    O Kargiotis, C Chetty, C S Gondi, S S Lakka & J S Rao

  2. Department of Neurosurgery, University of Illinois College of Medicine at Peoria, Peoria, IL, USA

    A J Tsung, D H Dinh & J S Rao

  3. Department of Pathology, University of Illinois College of Medicine at Peoria, Peoria, IL, USA

    M Gujrati

  4. Department of Neurology, University of Ioannina Medical School, Ioannina, Greece

    A P Kyritsis

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  1. O Kargiotis
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Correspondence to J S Rao.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Kargiotis, O., Chetty, C., Gondi, C. et al. Adenovirus-mediated transfer of siRNA against MMP-2 mRNA results in impaired invasion and tumor-induced angiogenesis, induces apoptosis in vitro and inhibits tumor growth in vivo in glioblastoma. Oncogene 27, 4830–4840 (2008). https://doi.org/10.1038/onc.2008.122

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