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Abstract
Substantial data indicate that microRNA 21 (miR-21) is significantly elevated in glioblastoma (GBM) and in many other tumors of various origins. This microRNA has been implicated in various aspects of carcinogenesis, including cellular proliferation, apoptosis, and migration. We demonstrate that miR-21 regulates multiple genes associated with glioma cell apoptosis, migration, and invasiveness, including the RECK and TIMP3 genes, which are suppressors of malignancy and inhibitors of matrix metalloproteinases (MMPs). Specific inhibition of miR-21 with antisense oligonucleotides leads to elevated levels of RECK and TIMP3 and therefore reduces MMP activities in vitro and in a human model of gliomas in nude mice. Moreover, downregulation of miR-21 in glioma cells leads to decreases of their migratory and invasion abilities. Our data suggest that miR-21 contributes to glioma malignancy by downregulation of MMP inhibitors, which leads to activation of MMPs, thus promoting invasiveness of cancer cells. Our results also indicate that inhibition of a single oncomir, like miR-21, with specific antisense molecules can provide a novel therapeutic approach for “physiological” modulation of multiple proteins whose expression is deregulated in cancer.
SUPPLEMENTAL MATERIAL
Supplemental material for this article may be found at http://mcb.asm.org/ .
ACKNOWLEDGMENTS
We thank Xandra O. Breakefield for helpful discussions and use of her laboratory facilities (GTBT CA6924) and Ralph Weissleder for providing the MMP probe and access to the Imaging Facility (NIH-NCI P50 CA86355-04). We thank John Pham for significant intellectual and experimental contribution to this work. A plasmid coding for the luciferase reporter of miR-21 activity was a kind gift from Ambion.
This study was supported by NCI R21CA116141 and Brain Tumor Society grants (to A.M.K.), a Paul Brazen American Brain Tumor Association Fellowship (to G.G.), and a Steve Kaplan American Brain Tumor Association Fellowship (to T.W.).