title: Interferon regulatory factor 7 regulates glioma stem cells via interleukin-6 and Notch signalling.
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.
authors.affiliation: School of Life Sciences and Biotechnology, Korea University, 5-ga, Anam-dong, Seongbuk-gu, Seoul 136-713, Republic of Korea.
authors.forename: Xun
authors.initials: X
authors.lastname: Jin
authors.forename: Sung-Hak
authors.initials: SH
authors.lastname: Kim
authors.forename: Hye-Min
authors.initials: HM
authors.lastname: Jeon
authors.forename: Samuel
authors.initials: S
authors.lastname: Beck
authors.forename: Young-Woo
authors.initials: YW
authors.lastname: Sohn
authors.forename: Jinlong
authors.initials: J
authors.lastname: Yin
authors.forename: Jun-Kyum
authors.initials: JK
authors.lastname: Kim
authors.forename: Young Chang
authors.initials: YC
authors.lastname: Lim
authors.forename: Jun-Han
authors.initials: JH
authors.lastname: Lee
authors.forename: Se-Hyuk
authors.initials: SH
authors.lastname: Kim
authors.forename: Shin-Hyuk
authors.initials: SH
authors.lastname: Kang
authors.forename: Xumin
authors.initials: X
authors.lastname: Pian
authors.forename: Min-Suk
authors.initials: MS
authors.lastname: Song
authors.forename: Jong Bae
authors.initials: JB
authors.lastname: Park
authors.forename: Yang-Seok
authors.initials: YS
authors.lastname: Chae
authors.forename: Yong-Gu
authors.initials: YG
authors.lastname: Chung
authors.forename: Seung-Hoon
authors.initials: SH
authors.lastname: Lee
authors.forename: Yun-Jaie
authors.initials: YJ
authors.lastname: Choi
authors.forename: Do-Hyun
authors.initials: DH
authors.lastname: Nam
authors.forename: Young Ki
authors.initials: YK
authors.lastname: Choi
authors.forename: Hyunggee
authors.initials: H
authors.lastname: Kim
mesh_terms: D000071916:AC133 Antigen; D015703:Antigens, CD / Q000378:metabolism; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000166:cytology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D054360:Chemokine CXCL1 / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D019295:Computational Biology; D042783:Endothelial Cells; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D005910:Glioma / Q000473:pathology*; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D050839:Interferon Regulatory Factor-7 / Q000235:genetics / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000502:physiology*; D009389:Neovascularization, Pathologic / Q000139:chemically induced / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D058953:Neural Stem Cells / Q000502:physiology; D010455:Peptides / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051881:Receptor, Notch1 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014161:Transduction, Genetic / Q000379:methods; D014410:Tumor Stem Cell Assay
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D018932:Chemokine CCL2; D054360:Chemokine CXCL1; D006023:Glycoproteins; D050839:Interferon Regulatory Factor-7; D015850:Interleukin-6; C497761:NOTCH1 protein, human; D009419:Nerve Tissue Proteins; D010455:Peptides; D034741:RNA, Small Interfering; D051881:Receptor, Notch1