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J Neurosurg. 2017 Jan;126(1):249-259. doi: 10.3171/2015.11.JNS15432. Epub 2016 Mar 11.

Bioinformatic analyses reveal a distinct Notch activation induced by STAT3 phosphorylation in the mesenchymal subtype of glioblastoma.

Cheng W1,2, Zhang C3,4,2, Ren X5, Jiang Y1,2, Han S1,2, Liu Y1,2, Cai J2,6, Li M3,4,2, Wang K2,7, Liu Y3,4,2, Hu H3,2, Li Q2,6, Yang P3,4,2, Bao Z4,2, Wu A1,2.

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Department of Neurosurgery, The First Hospital of China Medical University.
Chinese Glioma Cooperative Group (CGCG), Beijing.
Beijing Neurosurgical Institute, Capital Medical University, Beijing.
Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University.
Department of Pathology, Shengjing Hospital of China Medical University, Shenyang.
Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin; and.
Department of Neurosurgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China.


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.


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


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