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

Xun Jin, Sung Hak Kim, Hye Min Jeon, Samuel Beck, Young Woo Sohn, Jinlong Yin, Jun Kyum Kim, Young Chang Lim, Jun Han Lee, Se Hyuk Kim, Shin Hyuk Kang, Xumin Pian, Min Suk Song, Jong Bae Park, Yang Seok Chae, Yong Gu Chung, Seung Hoon Lee, Yun Jaie Choi, Do Hyun Nam, Young Ki ChoiHyunggee Kim

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41 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1055-1069
Number of pages15
JournalBrain
Volume135
Issue number4
DOIs
Publication statusPublished - 2012 Apr

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Keywords

  • angiogenesis
  • glioma stem cells
  • interferon regulatory factor 7
  • interleukin 6
  • tumour microenvironment

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Jin, X., Kim, S. H., Jeon, H. M., Beck, S., Sohn, Y. W., Yin, J., Kim, J. K., Lim, Y. C., Lee, J. H., Kim, S. H., Kang, S. H., Pian, X., Song, M. S., Park, J. B., Chae, Y. S., Chung, Y. G., Lee, S. H., Choi, Y. J., Nam, D. H., ... Kim, H. (2012). Interferon regulatory factor 7 regulates glioma stem cells via interleukin-6 and Notch signalling. Brain, 135(4), 1055-1069. https://doi.org/10.1093/brain/aws028