Xun Jin1,*, Sung-Hak Kim1,*, Hye-Min Jeon1,*, Samuel Beck2, Young-Woo Sohn1, Jinlong Yin2, Jun-Kyum Kim1, Young Chang Lim3, Jun-Han Lee4, Se-Hyuk Kim5, Shin-Hyuk Kang6, Xumin Pian1, Min-Suk Song4, Jong Bae Park7, Yang-Seok Chae8, Yong-Gu Chung6, Seung-Hoon Lee7, Yun-Jaie Choi2, Do-Hyun Nam9, Young Ki Choi4 and Hyunggee Kim1
1 School of Life Sciences and Biotechnology, Korea University, Seoul 136-713, Republic of Korea
2 School of Agricultural Biotechnology, Seoul National University, Seoul 151-921, Republic of Korea
3 Department of Otorhinolaryngology-Head and Neck Surgery, Research Institute of Medical Science, Konkuk University School of Medicine, Seoul 143-729, Republic of Korea
4 College of Medicine and Medical Research Institute, Chungbuk National University, Chongju 361-763, Republic of Korea
5 Department of Neurosurgery, School of Medicine, Ajou University, Suwon 443-721, Republic of Korea
6 Department of Neurosurgery, College of Medicine, Korea University, Seoul 136-705, Republic of Korea
7 Specific Organs Cancer Division, Research Institute and Hospital, National Cancer Centre, Goyang 410-769, Republic of Korea
8 Department of Pathology, College of Medicine, Korea University, Seoul 136-705, Republic of Korea
9 Department of Neurosurgery, Samsung Medical Centre and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul 135-710, Republic of Korea
* These authors contributed equally to this work.
Correspondence to: Hyunggee Kim, PhD, School of Life Sciences and Biotechnology, Korea University, 5-ga, Anam-dong, Seongbuk-gu, Seoul 136-713, Republic of Korea
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.
glioma stem cells, angiogenesis, interferon regulatory factor 7, interleukin 6, tumour microenvironment