OBJECTIVE Glioblastoma (GBM) is the most common and lethal type of malignant glioma. The Cancer Genome Atlas divides the gene expression-based classification of GBM into classical, mesenchymal, neural, and proneural subtypes, which is important for understanding GBM etiology and for designing effective personalized therapy. Signal transducer and activator of transcription 3 (STAT3), a critical transcriptional activator in tumorigenesis, is persistently phosphorylated and associated with an unfavorable prognosis in GBM. Although a set of specific targets has been identified, there have been no systematic analyses of STAT3 signaling based on GBM subtype. METHODS This study compared STAT3-associated messenger RNA, protein, and microRNA expression profiles across different subtypes of GBM. RESULTS The analyses revealed a prominent role for STAT3 in the mesenchymal but not in other GBM subtypes, which can be reliably used to classify patients with mesenchymal GBM into 2 groups according to phosphorylated STAT3 expression level. Differentially expressed genes suggest an association between Notch and STAT3 signaling in the mesenchymal subtype. Their association was validated in the U87 cell, a malignant glioma cell line annotated as mesenchymal subtype. Specific associated proteins and microRNAs further profile the STAT3 signaling among GBM subtypes. CONCLUSIONS These findings suggest a prominent role for STAT3 signaling in mesenchymal GBM and highlight the importance of identifying signaling pathways that contribute to specific cancer subtypes.
Keywords: AKT = protein kinase B; EGFR= epidermal growth factor receptor; GBM = glioblastoma; GO = gene ontology; GSEA = Gene Set Enrichment Analysis; JAK = Janus kinase; KEGG = Kyoto Encyclopedia of Genes and Genomes; MAPK = mitogen-activated protein kinase; Notch signaling; RIPA = radioimmunoprecipitation assay; RNAi = RNA interference; RPPA = reverse-phase protein array; RTK = receptor tyrosine kinase; STAT3; STAT3 = signal transducer and activator of transcription 3; TCGA; TCGA = The Cancer Genome Atlas; TGF-β = transforming growth factor–β; The Cancer Genome Atlas; activation; glioblastoma; mRNA = messenger RNA; mTOR = mammalian target of rapamycin; mesenchymal subtype; miRNA = microRNA; oncology; p-STAT3 = phosphorylated-STAT3; siRNA = short interfering RNA; signal transducer and activator of transcription 3; subtypes.