Abstract
Abstract Glioma (Glioblastoma multiforme, GBM) is the most common and the most aggressive form of brain tumor. As its Latin name implies, glioma is characterized by enormous heterogeneity and many different genes and cellular pathways responsible for glioma genesis and progression have been described. One of them is Sphingosine Kinase-1 (SPHK-1), a bona fide oncogene in glioma, whose marked up-regulation of expression and activity is responsible for the poor patient outcome due to escalating proliferation and invasiveness of glioma cells. MicroRNAs are short, non-coding regulators of the gene expression and deregulation of their expression is a frequent event in the formation and progression of many malignancies including glioma. Among these deregulated microRNAs, microRNA-124 is the most downregulated microRNA. It has been shown to promote neuronal differentiation and inhibit glioma cell proliferation and to target CDK6. Here we show that microRNA-1 is also severely downregulated in glioma patients and that it acts coordinately with microRNA-124 to target SPHK-1. We show that both microRNAs directly target the SPHK-1 3’UTR and that such targeting results in the decrease of both SPHK-1 expression and activity. We also demonstrate that overexpression of both microRNA-124 and microRNA-1 causes a significant increase in the frequency of apoptotic cells and marked decrease in glioma cell proliferation and invasiveness. Additionally, we show that microRNA-1 directly targets another glioma oncogene – Annexin2A (ANXA2). Targeting of ANXA2 by microRNA-1 impairs glioma cell-cell adhesion and glioma spheroid formation, which effect can be partially rescued by the overexpression of ANXA2 with a mutated microRNA-1 target site but not by wild type ANXA2. Our results provide another target of therapeutic importance for microRNA-124 in glioma cells. Here we show that microRNA-124, along with microRNA-1 can exert profound effect on glioma cells by inhibiting expression and activity of SPHK1 and that additional effects caused by microRNA-1 are likely mediated through targeting ANXA2. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3963. doi:10.1158/1538-7445.AM2011-3963
Published Version
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