Abstract
Long non-coding RNAs (lncRNAs) can function as competing endogenous RNAs (ceRNAs) that rewire post-transcriptional regulation in glioblastoma (GBM). Previous GBM studies have focused on either single lncRNA ceRNA axis in isolation or used in silico predictions with small patient cohorts (< 200). In this study, we integrated RNA-seq data from 372 TCGA-GBM tumors, 5 matched adjacent TCGA-normal brain and 2 931 GTEx-normal brain (n = 3 308) samples to build an experimentally informed ceRNA atlas. Limma-voom differential analysis, intersection with 2 experimentally supported interaction databases (ENCORI and miRTarBase) distilled 517 high-confidence lncRNA-miRNA-mRNA triplets. Twelve hub lncRNAs coordinated 3 downregulated miRNAs and 262 target mRNAs enriched for cell-cycle, p53 signaling and homologous recombination pathways. Two co-expressed hubs, CYTOR and MIR4435-2HG, were significantly over-expressed in GBM tumors in comparison with normal brain tissue and independently predicted poor overall survival (log-rank P < .01). Their shared 25 targets include oncogenic YBX1, MDM4 and TGFBR1 mRNAs, underscoring the redundant regulation of oncogenic pathways, suggesting the need to explore combination lncRNA inhibition strategies. This population-scale analysis prioritizes CYTOR and MIR4435-2HG for functional interrogation and offers a framework for exploring biomarkers and RNA-targeted strategies in GBM.