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MMP-9, uPAR and cathepsin B silencing downregulate integrins in human glioma xenograft cells in vitro and in vivo in nude mice

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Title: MMP-9, uPAR and cathepsin B silencing downregulate integrins in human glioma xenograft cells in vitro and in vivo in nude mice
Author(s): Veeravalli, Krishna Kumar; Chetty, Chandramu; Ponnala, Shivani; Gondi, Christopher S.; Lakka, Sajani S.; Fassett, Daniel; Klopfenstein, Jeffrey D.; Dinh, Dzung H.; Gujrati, Meena; Rao, Jasti S.
Subject(s): extracellular matrix cancer
Abstract: Background Involvement of MMP-9, uPAR and cathepsin B in adhesion, migration, invasion, proliferation, metastasis and tumor growth has been well established. In the present study, MMP-9, uPAR and cathepsin B genes were downregulated in glioma xenograft cells using shRNA plasmid constructs and we evaluated the involvement of integrins and changes in their adhesion, migration and invasive potential. Methodology/Principal Findings MMP-9, uPAR and cathepsin B single shRNA plasmid constructs were used to downregulate these molecules in xenograft cells. We also used MMP-9/uPAR and MMP-9/cathepsin B bicistronic constructs to evaluate the cumulative effects. MMP-9, uPAR and cathepsin B downregulation significantly inhibits xenograft cell adhesion to several extracellular matrix proteins. Treatment with MMP-9, uPAR and cathepsin B shRNA of xenografts led to the downregulation of several alpha and beta integrins. In all the assays, we noticed more prominent effects with the bicistronic plasmid constructs when compared to the single plasmid shRNA constructs. FACS analysis demonstrated the expression of αVβ3, α6β1 and α9β1 integrins in xenograft cells. Treatment with bicistronic constructs reduced αVβ3, α6β1 and α9β1 integrin expressions in xenograft injected nude mice. Migration and invasion were also inhibited by MMP-9, uPAR and cathepsin B shRNA treatments as assessed by spheroid migration, wound healing, and Matrigel invasion assays. As expected, bicistronic constructs further inhibited the adhesion, migration and invasive potential of the xenograft cells as compared to individual treatments. Conclusions/Significance Downregulation of MMP-9, uPAR and cathespin B alone and in combination inhibits adhesion, migration and invasive potential of glioma xenografts by downregulating integrins and associated signaling molecules. Considering the existence of integrin inhibitor-resistant cancer cells, our study provides a novel and effective approach to inhibiting integrins by downregulating MMP-9, uPAR and cathepsin B in the treatment of glioma.
Issue Date: 2010-07-15
Publisher: Public Library of Science
Citation Info: Veeravalli, K. K., Chetty, C., Ponnala, S., Gondi, C. S., Lakka, S. S., Fassett, D., Klopfenstein, J. D., Dinh, D. H., Gujrati, M., & Rao, J. S. 2010. MMP-9, uPAR and cathepsin B silencing downregulate integrins in human glioma xenograft cells in vitro and in vivo in nude mice. PLoS One, 5(7): e11583. DOI: 10.1371/journal.pone.0011583
Type: Article
Description: The original source for this publication is at Public Library of Science; DOI: 10.1371/journal.pone.0011583. © 2010 Veeravalli et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
URI: http://hdl.handle.net/10027/7647
ISSN: 1932-6203
Sponsor: This research was supported by a grant from the National Institute of Neurological Disorders and Stroke (NINDS NS047699). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Date Available in INDIGO: 2011-05-25
 

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