Dihydropyrimidinase-related protein 5 controls glioblastoma stem cell characteristics as a biomarker of proneural-subtype glioblastoma stem cells

Abstract

Glioblastoma (GBM) is the most aggressive and malignant brain tumor, resulting in a poor prognosis. The current therapy for GBM consists in concurrent radiation and chemotherapy following removal of the tumor. Although the therapy prolongs patient survival, recurrence often occurs. The major cause of tumor recurrence is thought to be GBM stem cells (GSCs), which aid the development of chemo-radiotherapy resistance, and can self-renew and aberrantly differentiate. Therefore, GSCs should be targeted to eradicate the tumor and prevent recurrence. Transcriptomic analysis has categorized GBM into proneural (PN), mesenchymal and classical subtypes, and the outcome of recurrence and prognosis markedly depends on subtype. To identify specific GSC markers, the present study analyzed public microarray and RNA-seq data and identified dihydropyrimidinase-related protein 5 (DRP5) as a candidate GSC marker. DRP5 is known to mediate semaphorin 3A signaling and is involved in the regulation of neurite outgrowth and axon guidance during neuronal development. In the present study, DRP5 was specifically upregulated in the PN-subtype GSCs and served crucial roles in maintaining GSC properties, including tumor sphere formation, stem cell marker expression and xenograft tumor growth. Furthermore, bioinformatics analysis revealed that DRP5 expression was positively correlated with signatures of stemness, including Notch, Hedgehog and Wnt/beta -catenin expression, which are also known to be positively correlated with PN-subtype gene signatures. Conversely, DRP5 expression was negatively correlated with NF-kappa B and signal transducer and activator of transcription 3 stemness signatures, which are negatively correlated with PN-subtype gene signatures. Taken together, these findings suggested that DRP5 was specifically expressed in PN-subtype GSCs and may be used as a functional marker of PN-subtype GSCs.