Abstract 2050: MicroRNA-124a: A master regulator of glioblastoma migration

Abstract

Abstract For most patients diagnosed with a glioblastoma multiforme (GBM), the invasiveness of this tumor and its resistance to treatment predicts a poor outcome with no realistic possibility of a cure. Although brain tumor cells rarely metastasize outside the brain, they have an extraordinary capacity to migrate long distances and infiltrate normal brain, making complete surgical removal impossible. New therapeutic strategies are needed to target the invading cell population to further reduce tumor cell spread and a better understanding of the mechanisms promoting tumor migration and invasion are urgently needed. MiR-124a, a microRNA, normally abundantly expressed in normal adult brain tissue, shows marked down regulation (>1000 fold) in GBM cell lines (A172, T98G, MO59J, MO59K and U87MG). Conversely, a predicted miR-124a target, IQGAP1, is over-expressed in GBM cell lines and tissue samples. We previously demonstrated IQGAP1 overexpression in 86% of GBM patients and associated high levels with poor prognosis. IQGAP1 expression was prominent in the actively migrating and rapidly dividing palisading neoplastic cells that surround the necrotic foci. We hypothesized a reciprocal interaction between miR-124a and IQGAP1. To show this, GBM cell lines were transfected with a synthetic miR-124a precursor molecule to increase endogenous miR-124a expression. Cell migration was measured by impedence of a current (ECIS 9600) and tumor cell invasion was measured using transwell inserts. The interaction between miR-124a and IQGAP1 was ascertained using quantitative PCR, Western Blot analysis and luciferase reporter assays. Transfected miR-124a-GBM cells did not show any alterations in cell proliferation however significant reductions in tumor cell migration and invasion were observed when compared to control cells. Reducedmigration and invasion was also observed when GBM cells were transiently transfected with siRNA directed at IQGAP1. A direct effect of miR-124a on IQGAP1 expression levels was demonstrated at the mRNA and protein levels via miR-124a targeting the IQGAP1 mRNA 3’-UTR. In summary, we show that miR-124 functions as a tumour suppressor miRNA being downregulated in GBM which results in overexpression of IQGAP1. Additional migratory proteins commonly overexpressed in GBM also possess predicted miR-124a target sites and are currently been evaluated. miR-124a may therefore act as a master regulator of GBM invasiveness. Furthermore, delivery of miR-124a into GBMs may represent as a novel therapeutic approach to limit GBM invasion both alone and in combination with convential chemotherapy treatments. 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 2050.