MiR-21 Promotes Glioma Invasion by Targeting MMP Regulators.

Substantial data indicate that microRNA-21 (miR-21) is significantly elevated in glioblastoma (GBM) and in many other tumors of various origins. This miRNA 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 RECK and TIMP3, suppressors of malignancy and inhibitors of matrix metalloproteinases (MMPs). Specific inhibition of miR-21 with antisense olgonucleotides leads to elevated levels of RECK and TIMP3 and therefore reduces MMP activities in vitro and in a human model of glioma in nude mice. Moreover, down-regulation of miR-21 in glioma cells leads to decrease of their migratory and invasion abilities. Our data suggest that miR-21 contributes to the glioma malignancy by down-regulation of MMP inhibitors that 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 de-regulated in cancer. A172 glioma cells treated with anti-miR-21, mismatch control antagomiR, or miR-21 mimetic duplex were compared to mock-treated A172 glioma cells as a reference. Cells were harvested at 6 and 24 hours post-treatment, comprising six pairs of samples in all. No replicate samples are included. Agilent microarrays (anti-miR-21, mismatch control antagomiR,and matching mock treatments) were hybridized as fluor-reversed pairs of arrays. Affymetrix microarrays were hybridized as single technical replicates.