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J. Biol. Chem., Vol. 280, Issue 23, 21882-21892, June 10, 2005

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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^*

Sajani S. Lakka, Christopher S. Gondi, Dzung H. Dinh¶, William C. Olivero¶, Meena Gujrati||, Velidi H. Rao**, Chrissa Sioka, and Jasti S. Rao¶

From the Departments of Biomedical and Therapeutic Sciences (Program of Cancer Biology), ^¶Neurosurgery, and ^||Pathology, College of Medicine, University of Illinois, Peoria, Illinois 61656, the ^**Department of Genetics, Boystown National Research Hospital, Omaha, Nebraska 68131, and the Department of Nuclear Medicine, 417 Army Share Found Hospital, Athens 11521, Greece

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.

Received for publication, July 27, 2004 , and in revised form, April 5, 2005.

^* This work was supported by NCI, National Institutes of Health (NIH) Grants CA75557 and CA92393 and NINDS, NIH Grant NS47699 (to J. S. R.) and by Caterpillar, Inc., Peoria, IL (to J. S. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to this work.

To whom correspondence should be addressed: Dept. of Biomedical and Therapeutic Sciences, Box 1649, Peoria, IL 61656. Tel.: 309-671-3445; Fax: 309-671-3442; E-mail: jsrao{at}uic.edu.

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