STEM-39. TRANSCRIPTOME ANALYSIS OF GLIOMA STEM-LIKE CELLS REVEALS SOX2 REGULATES miR-425-5p EXPRESSION

Glioblastoma is the most common malignant primary brain tumors in adults, and despite established therapeutic approaches, the prognosis remains bleak. Glioblastoma tumors are composed of heterogeneous cell populations, among which the glioma stem-like cells (GSCs) are crucial to tumor self-renewal, growth, and recurrence. The transcription factor sex determining region Y-box 2 (SOX2) is enriched in GSCs where it controls stemness, invasion, and maintenance of tumorigenicity. Therefore, defining the molecular mechanisms governed by SOX2 in GSCs is critical to developing targeted therapies against this recalcitrant population. In this study, we performed a genome-wide analysis of SOX2-regulated coding and non-coding transcripts in GSCs. We identified 2,048 differentially expressed coding transcripts regulated by SOX2. These genes are involved in diverse biological processes, such as cell adhesion, intercellular signal transduction, canonical intracellular signaling cascades (KITLG, GHR, IRS1, HES5, HEY1), and amino-acid metabolism. Additionally, SOX2 was found to differentially regulate 261 non-coding transcripts in GSCs, including miRNAs and lncRNAs. Of particular interest, we identified miR-425-5p as a robust and significant validated candidate for further study. The expression of miR-425-5p was significantly overexpressed in glioblastoma tissue and correlate with SOX2 expression (R2= 0.70; p= 0.01). Using chromatin immunoprecipitation assay followed by qRT-PCR we found that SOX2 activated miR-425-5p expression by directly binding to its promoter. Conversely, inhibition of miR-425-5p expression, using a miRNA sponge lentiviral vector, prevented neurosphere formation, cell proliferation, and promotes apoptosis. Impairing miR-425-5p expression in vivo leads to a significant increase in overall median survival time of nude mice harboring orthotopic glioma xenografts. In summary, this research is the first to identify transcriptional programs controlled by SOX2 in GSCs. In doing so, we defined miR-425-5p as a novel potential onco-miR in GSCs. Taken together, our studies have provided new insights regarding the molecular circuitries governing glioblastoma biology.