Abstract Glioblastoma multiforme (GBM) is the most frequent brain tumor in adults and is the most lethal form of human cancer. Despite the improvements in treatments, patients's survival remains poor. Different evidences indicate that microRNAs might play a fundamental role in tumorigenesis, cell proliferation, migration and apoptosis. Through a microarray analysis we identified different microRNAs upregulated in the tumorigenic glioma cell lines U87 compared with the non tumorigenic cell lines T98G. Among different microRNAs we focused our attention on miR221&222. By bioinformatic analysis we identified a binding site for these two miRs in the 3′UTR of the protein phosphatase PTPμ. Luciferase assay confirmed that miR-221 and 222 bind to the 3′UTR of PTPμ and impairs its mRNA translation. Previous studies indicated that PTPμ suppresses cell migration/invasion and is downregulated in glioma. Significantly, we found that miR 221&222 overexpression induced a downregulation of PTPμ as analyzed by both western blot and RT-PCR. Furthermore, miR222&221 induced an increase in cell migration/invasion in glioma cells. Accordingly, we found an inverse correlation between miR221&222 and PTPμ in glioma cancer samples, as analyzed by immunohistochemistry and in situ hybridization on a tissue array representing 46 glioma and normal brain tissues. In conclusion, our results suggest that microRNA 221&222 might regulate glioma tumorigenesis through the control of cell migration process. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-351.