Abstract LB-339: MicroRNA modulators regulate oncogenes and tumor suppressors in glioblastoma

Abstract

Abstract MicroRNAs, including miR-21, MiR-26a and miR-221/2, are potential key regulators of gene expression in glioblastoma, the most common and the most aggressive type of primary human brain tumor. Their activity is modulated by post-transcriptional factors that regulate mRNA processing pathways and by the abundance of their targets. Despite recent efforts to identify microRNA modulators, this mode of regulation is still poorly understood, and the repertoire and extent that microRNA modulators regulate gene expression in tumors and affect tumorigenesis remain unknown. We developed a genome-wide approach to identify glioblastoma-specific microRNA modulators. We identified hundreds of candidate modulators, including modulators that either activate or suppress miRISC-mediated regulation, and mRNAs that act as decoys and compete for microRNA binding in glioblastoma. Validation experiments were done in SNB19 cell line by measuring differential expression of mature microRNAs and their targets after ectopic expression or inhibition of predicted regulator proteins. 3′ UTR luciferase assays were used to establish the post-transcriptional nature of the regulation. Focusing on two known drivers of gliomagenesis and progression, we showed that PTEN is post-transcriptionally up regulated by WNT7A through miR-21 and down regulated by PALB2 through miR-106a, and that RUNX1 is post-transcriptionally down regulated by WIPF2 through miR-17–5p. Further, we showed that PTEN and RUNX1, which are widely considered functionally unrelated, act as decoys for one another by competing for a common microRNA-regulatory program: they post-transcriptionally regulate one another through their microRNA regulators. In addition, other modulators with prognosis-predictive genetic alterations act through common microRNA-regulatory programs to regulate PTEN and RUNX1 expression. For example, prognosis-predictive genetic alterations at the CTBP2 locus significantly alter both CTBP2 and PTEN expression in glioblastoma; siRNA-mediated silencing of CTBP2 resulted in a 30% reduction in the expression of PTEN 3′ UTR luciferase reporters. Our results demonstrate that microRNA modulators regulate the expression of key glioblastoma drivers, and that genetic alterations at microRNA modulators lead to aberrant post-transcriptional regulation of these drivers. Taken together, these results suggest that microRNA modulation plays a significant role in tumorigenesis and progression of gliobalstoma. 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 LB-339. doi:10.1158/1538-7445.AM2011-LB-339