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Molecular and Cellular Biology, September 2008, p. 5369-5380, Vol. 28, No. 17
0270-7306/08/$08.00+0     doi:10.1128/MCB.00479-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

MicroRNA 21 Promotes Glioma Invasion by Targeting Matrix Metalloproteinase Regulators ^,

Galina Gabriely,^1, Thomas Wurdinger,^2,3,4, Santosh Kesari,^1,5 Christine C. Esau,⁶ Julja Burchard,⁷ Peter S. Linsley,⁷ and Anna M. Krichevsky^1*

Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts,¹ Departments of Neurology and Radiology, Massachusetts General Hospital and Neuroscience Program, Harvard Medical School, Boston, Massachusetts,² Center for Molecular Imaging Research, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts,³ Neuro-Oncology Research Group, Cancer Center Amsterdam, VU Medical Center, Amsterdam, The Netherlands,⁴ Center for Neuro-Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts,⁵ Regulus Therapeutics, Carlsbad, California,⁶ Rosetta Inpharmatics, LLC, Seattle, Washington⁷

Received 23 March 2008/ Returned for modification 9 June 2008/ Accepted 20 June 2008

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.

Published ahead of print on 30 June 2008.

Supplemental material for this article may be found at http://mcb.asm.org/.

Equal contribution.