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Interferon regulatory factor 7 regulates glioma stem cells via interleukin-6 and Notch signalling

Authors
Jin, X; Kim, SH; Jeon, HM; Beck, S; Sohn, YW; Yin, J; Kim, JK; Lim, YC; Lee, JH; Kang, SH; Pian, X; Song, MS; Park, JB; Chae, YS; Chung, YG; Lee, SH; Choi, YJ; Nam, DH; Choi, YK; Kim, H
Citation
Brain : a journal of neurology, 135(Pt 4):1055-1069, 2012
Journal Title
Brain : a journal of neurology
ISSN
0006-89501460-2156
Abstract
Inflammatory microenvironment signalling plays a crucial role in tumour progression (i.e. cancer cell proliferation, survival, angiogenesis and metastasis) in many types of human malignancies. However, the role of inflammation in brain tumour pathology remains poorly understood. Here, we report that interferon regulatory factor 7 is a crucial regulator of brain tumour progression and heterogeneity. Ectopic expression of interferon regulatory factor 7 in glioma cells promotes tumorigenicity, angiogenesis, microglia recruitment and cancer stemness in vivo and in vitro through induction of interleukin 6, C-X-C motif chemokine 1 and C-C motif chemokine 2. In particular, interferon regulatory factor 7-driven interleukin 6 plays a pivotal role in maintaining glioma stem cell properties via Janus kinase/signal transducer and activator of transcription-mediated activation of Jagged-Notch signalling in glioma cells and glioma stem cells derived from glioma patients.  Accordingly, the short hairpin RNA-mediated depletion of interferon regulatory factor 7 in glioma stem cells markedly suppressed interleukin 6-Janus kinase/signal transducer and activator of transcription-mediated Jagged-Notch-signalling pathway, leading to decreases in glioma stem cell marker expression, tumoursphere-forming ability, and tumorigenicity. Furthermore, in a mouse model of wound healing, depletion of interferon regulatory factor 7 suppressed tumour progression and decreased cellular heterogeneity. Finally, interferon regulatory factor 7 was overexpressed in patients with high-grade gliomas, suggesting its potential as an independent prognostic marker for glioma progression. Taken together, our findings indicate that interferon regulatory factor 7-mediated inflammatory signalling acts as a major driver of brain tumour progression and cellular heterogeneity via induction of glioma stem cell genesis and angiogenesis.
MeSH terms
Antigens, CD/metabolismAstrocytes/metabolismBrain/cytologyCell Line, TumorCell Movement/physiologyCell ProliferationCells, CulturedChemokine CCL2/metabolismChemokine CXCL1/metabolismChromatin ImmunoprecipitationComputational BiologyEndothelial CellsGene Expression Regulation, Neoplastic/drug effects/geneticsGlioma/*pathologyGlycoproteins/metabolismHumansInterferon Regulatory Factor-7/genetics/*metabolismInterleukin-6/*metabolismNeoplastic Stem Cells/*physiologyNeovascularization, Pathologic/chemically induced/metabolismNerve Tissue Proteins/metabolismNeural Stem Cells/physiologyPeptides/metabolismRNA, Small Interfering/genetics/metabolismReceptor, Notch1/*metabolismSignal Transduction/*physiologyTransduction, Genetic/methodsTumor Stem Cell Assay
DOI
10.1093/brain/aws028
PMID
22434214
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Neurosurgery
AJOU Authors
김, 세혁
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