Abstract 2946: Post-transcriptional regulators of microRNA biogenesis regulate pathogenesis of cancer

Abstract

Abstract MicroRNAs (miRs) have emerged as key regulators of both normal and pathologic phenotypes, including cancer. Fine grained regulation of their biogenesis, however, is still poorly understood and only a few of their key regulators have been characterized. In order to understand the extent and specificity of miR-biogenesis control, as well as the role of miR-biogenesis regulators in tumorigenesis and cancer progression, we set out to identify these regulators and profile their targets. We developed a genome-wide computational screening method that leverages miR and gene expression profiles in hundreds of samples to identify potential biogenesis regulators in glioma and ovarian cancer. In total, miRage predicted thirty miR-biogenesis regulators that are common to glioma and ovarian cancer tumors, and hundreds of glioma-specific and ovarian-cancer-specific regulators. Predicted regulators include known biogenesis regulators DGCR8, HNRNPA1, DDX5, LIN28 and SMAD family proteins. We validated selected regulators that are predicted to regulate miRs in both cancers and are differentially expressed across glioma prognosis. Differential expression of (1) mature miRs, (2) their host genes, (3) co-transcribed miRs, (4) miR precursors, and (5) pri-miRs were measured upon ectopic expression or RNAi-mediated silencing of the predicted regulators in a glioma cell line. DDX10 was predicted to up-regulate miR-218 biogenesis, and we showed that its ectopic expression up-regulates miR-218 at the pri-miRNA stage; up-regulation of DDX10 may account for miR-218 over-expression in poor-prognosis tumors. High-throughput screening by nanostring nCounter and fluidigm systems suggest that DDX10 regulation is broader effect than regulation by the known biogenesis regulator, DDX17. In total, we report on nearly a dozen validated miR-biogenesis regulators that were predicted by our computational screens. Our results suggest that miR biogenesis is a complex, context specific, and finely-regulated process, and that miR biogenesis regulators may influence tumor initiation and progression by altering the expression of specific tumor-suppressor and oncomirs or by modifying large miR programs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2946. doi:1538-7445.AM2012-2946