Document Detail


Specific interference of urokinase-type plasminogen activator receptor and matrix metalloproteinase-9 gene expression induced by double-stranded RNA results in decreased invasion, tumor growth, and angiogenesis in gliomas.
MedLine Citation:
PMID:  15824107     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
We have previously demonstrated the effectiveness of adenovirus-mediated expression of antisense urokinase-type plasminogen activator receptor (uPAR) and matrix metalloproteinase-9 (MMP-9) in inhibiting tumor invasion in vitro and ex vivo. However, the therapeutic effect of the adenovirus-mediated antisense approach was shown to be transient and required potentially toxic, high viral doses. In contrast, RNA interference (RNAi)-mediated gene targeting may be superior to the traditional antisense approach, because the target mRNA is completely degraded and the molar ratio of siRNA required to degrade the target mRNA is very low. Here, we have examined the siRNA-mediated target RNA degradation of uPAR and MMP-9 in human glioma cell lines. Using RNAi directed toward uPAR and MMP-9, we achieved specific inhibition of uPAR and MMP-9. This bicistronic construct (pUM) inhibited the formation of capillary-like structures in both in vitro and in vivo models of angiogenesis. We demonstrated that blocking the expression of these genes results in significant inhibition of glioma tumor invasion in Matrigel and spheroid invasion assay models. RNAi for uPAR and MMP-9 inhibited cell proliferation, and significantly reduced the levels of phosphorylated forms of MAPK, ERK, and AKT signaling pathway molecules when compared with parental and empty vector/scrambled vector-transfected SNB19 cells. Furthermore, using RNAi to simultaneously target two proteases resulted in total regression of pre-established intracerebral tumor growth. Our results provide evidence that the use of hairpin siRNA expression vectors for uPAR and MMP-9 may provide an effective tool for cancer therapy.
Authors:
Sajani S Lakka; Christopher S Gondi; Dzung H Dinh; William C Olivero; Meena Gujrati; Velidi H Rao; Chrissa Sioka; Jasti S Rao
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.     Date:  2005-04-11
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  280     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2005 Jun 
Date Detail:
Created Date:  2005-06-06     Completed Date:  2005-08-02     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  21882-92     Citation Subset:  IM    
Affiliation:
Departments of Biomedical and Therapeutic Sciences (Program of Cancer Biology), College of Medicine, University of Illinois, Peoria, IL 61656, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Brain Neoplasms / blood supply,  metabolism*,  pathology
Cell Line, Transformed
Cell Line, Tumor
Cell Proliferation
Collagen / pharmacology
Down-Regulation
Drug Combinations
Extracellular Signal-Regulated MAP Kinases / metabolism
Female
Gene Expression Regulation, Enzymologic*
Gene Silencing
Genetic Vectors
Glioblastoma / metabolism
Glioma / blood supply,  metabolism*,  therapy
Green Fluorescent Proteins / chemistry,  metabolism
Humans
Immunohistochemistry
Laminin / pharmacology
MAP Kinase Signaling System
Male
Matrix Metalloproteinase 9 / metabolism*
Mice
Mice, Nude
Models, Biological
Models, Genetic
Neoplasm Invasiveness
Neovascularization, Pathologic*
Nucleic Acid Conformation
Phosphorylation
Promoter Regions, Genetic
Protein Structure, Tertiary
Proteoglycans / pharmacology
RNA Interference*
RNA, Double-Stranded / genetics*
RNA, Small Interfering / metabolism
Receptors, Cell Surface / metabolism*
Receptors, Urokinase Plasminogen Activator
Time Factors
Transfection
Grant Support
ID/Acronym/Agency:
CA 75557/CA/NCI NIH HHS; CA 92393/CA/NCI NIH HHS; NS 47699/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
0/Drug Combinations; 0/Laminin; 0/PLAUR protein, human; 0/Plaur protein, mouse; 0/Proteoglycans; 0/RNA, Double-Stranded; 0/RNA, Small Interfering; 0/Receptors, Cell Surface; 0/Receptors, Urokinase Plasminogen Activator; 119978-18-6/matrigel; 147336-22-9/Green Fluorescent Proteins; 9007-34-5/Collagen; EC 2.7.11.24/Extracellular Signal-Regulated MAP Kinases; EC 3.4.24.35/Matrix Metalloproteinase 9

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