title: Bioinformatic analyses reveal a distinct Notch activation induced by STAT3 phosphorylation in the mesenchymal subtype of glioblastoma.
abstract: 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.
authors.affiliation: Department of Neurosurgery, The First Hospital of China Medical University.|Chinese Glioma Cooperative Group (CGCG), Beijing.
authors.forename: Wen
authors.initials: W
authors.lastname: Cheng
authors.affiliation: Beijing Neurosurgical Institute, Capital Medical University, Beijing.|Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University.|Chinese Glioma Cooperative Group (CGCG), Beijing.
authors.forename: Chuanbao
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Shengjing Hospital of China Medical University, Shenyang.
authors.forename: Xiufang
authors.initials: X
authors.lastname: Ren
authors.affiliation: Department of Neurosurgery, The First Hospital of China Medical University.|Chinese Glioma Cooperative Group (CGCG), Beijing.
authors.forename: Yang
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Neurosurgery, The First Hospital of China Medical University.|Chinese Glioma Cooperative Group (CGCG), Beijing.
authors.forename: Sheng
authors.initials: S
authors.lastname: Han
authors.affiliation: Department of Neurosurgery, The First Hospital of China Medical University.|Chinese Glioma Cooperative Group (CGCG), Beijing.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Chinese Glioma Cooperative Group (CGCG), Beijing.|Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin; and.
authors.forename: Jinquan
authors.initials: J
authors.lastname: Cai
authors.affiliation: Beijing Neurosurgical Institute, Capital Medical University, Beijing.|Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University.|Chinese Glioma Cooperative Group (CGCG), Beijing.
authors.forename: Mingyang
authors.initials: M
authors.lastname: Li
authors.affiliation: Chinese Glioma Cooperative Group (CGCG), Beijing.|Department of Neurosurgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
authors.forename: Kuanyu
authors.initials: K
authors.lastname: Wang
authors.affiliation: Beijing Neurosurgical Institute, Capital Medical University, Beijing.|Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University.|Chinese Glioma Cooperative Group (CGCG), Beijing.
authors.forename: Yanwei
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Beijing Neurosurgical Institute, Capital Medical University, Beijing.|Chinese Glioma Cooperative Group (CGCG), Beijing.
authors.forename: Huimin
authors.initials: H
authors.lastname: Hu
authors.affiliation: Chinese Glioma Cooperative Group (CGCG), Beijing.|Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin; and.
authors.forename: Qingbin
authors.initials: Q
authors.lastname: Li
authors.affiliation: Beijing Neurosurgical Institute, Capital Medical University, Beijing.|Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University.|Chinese Glioma Cooperative Group (CGCG), Beijing.
authors.forename: Pei
authors.initials: P
authors.lastname: Yang
authors.affiliation: Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University.|Chinese Glioma Cooperative Group (CGCG), Beijing.
authors.forename: Zhaoshi
authors.initials: Z
authors.lastname: Bao
authors.affiliation: Department of Neurosurgery, The First Hospital of China Medical University.|Chinese Glioma Cooperative Group (CGCG), Beijing.
authors.forename: Anhua
authors.initials: A
authors.lastname: Wu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D016543:Central Nervous System Neoplasms / Q000145:classification* / Q000235:genetics / Q000378:metabolism*; D019295:Computational Biology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000145:classification* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000378:metabolism; D046228:Microarray Analysis; D008875:Middle Aged; D010766:Phosphorylation / Q000502:physiology; D051880:Receptors, Notch / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D035683:MicroRNAs; D051880:Receptors, Notch; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human
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