BI-03 * GLIOBLASTOMA-SPECIFIC AND GLIOBLASTOMA STEM CELL SUBTYPE-SPECIFIC SIGNATURES OF LONG, NON-CODING RNAs

Abstract

Long-non coding RNAs (lncRNAs) are large and heterogeneous group of non-protein coding RNAs larger than 200nt. They regulate the expression of their target genes by multiple mechanisms including regulation of transcription, splicing, translation and epigenetic regulation. There is growing evidence of important role of lncRNAs in carcinogenesis, including glioblastoma multiforme (GBM). To profile lncRNAs in GBM patient samples and cells, we designed a platform using NanoString system to detect 73 lncRNAs that has been implicated in cancer pathophysiology. We used our collection of matched samples (i.e. from the same patient) of GBM tumors and adjacent brain tissue. We showed that 27-lncRNA signature (10 GBM-low and 17 GBM-high) clustered these samples. Glioblastoma stem cells (GSCs) are highly tumorigenic and therapy-resistant sub-population of glioblastoma. We characterized our large collection of patient-derived GSCs maintained in serum-free culture. Based on 10-gene signature we ascribed them to either proneural (PN), mesenchymal (MES) subtype. We demonstrated that 28-lncRNA signature (7 PN-low and 21 PN-high) clustered PN and MES GSCs. Testing the functionality of lncRNAs, we showed that PN-MES subtype switch achieved by de-regulation of important regulator of GSC self-renewal - miR-128, was concurrent with the shift in lncRNA signature. Finally, based on 29-lncRNA signature, we were able to establish that, irradiated PN GSCs acquired more mesenchymal characteristics. Our results thus suggest broad involvement of lncRNAs in the regulation of pathophysiological processes in GBM/GSC cells.