Blockage of a miR-21/EGFR regulatory feedback loop augments anti-EGFR therapy in glioblastomas

Epidermal growth factor receptors (EGFR) expression is frequently amplified in human glioblastoma cells. Nimotuzumab, a monoclonal antibody (mAb) against EGFR, has been used globally in clinics as an anticancer agent. It is largely unknown whether the blockade of miR-21, a microRNA that is upregulated in glioma cells, could amplify the effects of nimotuzumab. Herein, we have demonstrated that miR-21 directly targets von Hippel-Lindau (VHL) and peroxisome-proliferator-activated receptor alpha (PPAR alpha) and that miR-21 regulates EGFR/AKT signaling through VHL/beta-catenin and the PPAR alpha/AP-1 axis. Further, the expression of miR-21 is regulated by EGFR via the activation of beta-catenin and AP-1. These data indicate that a feedback loop exists between miR-21 and EGFR. We also show that the combination of nimotuzumab and an inhibitor of miR-21 is superior to single-agent therapy. These results clarify a novel association between miR-21 and EGFR in the regulation of cancer cell progression. (C) 2013 Elsevier Ireland Ltd. All rights reserved.