Abstract
Genomic, transcriptional, and proteomic analyses of brain tumors reveal that subtypes differ in their pathway activity, progression, and response to therapy. We performed an expression profiling of Glioma Initiating Cells (GICs) and comparative analysis between different groups of GICs indicates major variations in gene expression. Hierarchical clustering analysis revealed groups of GICs reflecting their heterogeneity, and among some of the genes as major regulators of mesenchymal phenotype, we identified ABOBEC3G as one of the most discriminating genes in mesenchymal group. ABOBEC3G revealed a strong correlation with overall survival in TCGA GBM patient cohorts. APOBEC3G regulates cell invasion and silencing of this gene in GICs inhibits cell invasion and also glioma sphere initiation. APOBEC3G controls invasion through TGFβ/Smad2 pathway by regulating Smad2 target genes Thrombospondin 1, matrix metallopeptidase 2 and TIMP metallopeptidase inhibitor 1. We also show that targeting APOBEC3G can sensitize cancer cells to radiation induced cell death by attenuating activation of the DNA repair pathway. This response is mainly shown by decreased pChk2 expression in knockdown APOBEC3G cells. Taken together, we show that APOBEC3G gene is a mesenchymal enriched gene that controls invasion and knockdown of APOBEC3G sensitizes cells to radiation induced cell death, suggesting that APOBEC3G can be considered for use in stratifying patients with GBM for prognostic considerations.
Highlights
Glioblastoma (GBM), the most common primary malignant tumor of the central nervous system [1], is most aggressive, with a dismal prognosis
Based on the transcriptome array analyses, we found that genes are differentially expressed between Mesenchymal Glioma Initiating Cells (GICs) and other non-Mesenchymal GICs
Applying a FDR of ≤ 0.01, we identified 89 genes significantly upregulated and 164 genes downregulated in mesenchymal GICs (Supplementary Dataset 1)
Summary
Glioblastoma (GBM), the most common primary malignant tumor of the central nervous system [1], is most aggressive, with a dismal prognosis. The median survival time of patients with GBM is less than 2 years despite standard care, composed of resection, concomitant radiotherapy plus temozolomide, and adjuvant chemotherapy with temozolomide [2]. The Cancer Genome Atlas (TCGA) divided GBM into four subtypes: classic, mesenchymal, neural, and proneural [5]. Transcriptional profiling studies by Phillips et al [6] and Verhaak et al [5] have revealed molecular subtypes of high-grade gliomas based on the expression of genes characteristic of proneural (PN), neural (N), classical www.impactjournals.com/oncotarget (CLAS) or mesenchymal (MES). A number of transcription factors, including C/EBP-β (CCAAT-enhancer-binding protein-β) and STAT3 (signal transducer and activator of transcription 3) and more recently the transcriptional coactivator TAZ (transcriptional coactivator with PDZ-binding motif), have been identified as important regulators of the mesenchymal phenotype in GBM [8, 9]
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