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

被引：70

作者：

Jin, Xun ^{[1
]}

Kim, Sung-Hak ^{[1
]}

Jeon, Hye-Min ^{[1
]}

Beck, Samuel ^{[2
]}

Sohn, Young-Woo ^{[1
]}

Yin, Jinlong ^{[2
]}

Kim, Jun-Kyum ^{[1
]}

Lim, Young Chang ^{[3
]}

Lee, Jun-Han ^{[4
,5
]}

Kim, Se-Hyuk ^{[6
]}

Kang, Shin-Hyuk ^{[7
]}

Pian, Xumin ^{[1
]}

Song, Min-Suk ^{[4
,5
]}

Park, Jong Bae ^{[8
]}

Chae, Yang-Seok ^{[9
]}

Chung, Yong-Gu ^{[7
]}

Lee, Seung-Hoon ^{[8
]}

Choi, Yun-Jaie ^{[2
]}

Nam, Do-Hyun ^{[10
,11
]}

Choi, Young Ki ^{[4
,5
]}

Kim, Hyunggee ^{[1
]}

机构：

[1] Korea Univ, Sch Life Sci & Biotechnol, Seoul 136713, South Korea

[2] Seoul Natl Univ, Sch Agr Biotechnol, Seoul 151921, South Korea

[3] Konkuk Univ, Sch Med, Res Inst Med Sci, Dept Otorhinolaryngol Head & Neck Surg, Seoul 143729, South Korea

[4] Chungbuk Natl Univ, Coll Med, Chonju 361763, South Korea

[5] Chungbuk Natl Univ, Med Res Inst, Chonju 361763, South Korea

[6] Ajou Univ, Sch Med, Dept Neurosurg, Suwon 443721, South Korea

[7] Korea Univ, Coll Med, Dept Neurosurg, Seoul 136705, South Korea

[8] Natl Canc Ctr, Res Inst & Hosp, Specif Organs Canc Div, Goyang 410769, South Korea

[9] Korea Univ, Coll Med, Dept Pathol, Seoul 136705, South Korea

[10] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Neurosurg, Seoul 135710, South Korea

[11] Sungkyunkwan Univ, Sch Med, Samsung Biomed Res Inst, Seoul 135710, South Korea

来源：

BRAIN | 2012年 / 135卷

关键词：

glioma stem cells; angiogenesis; interferon regulatory factor 7; interleukin; 6; tumour microenvironment; GROWTH-INHIBITION; STAT3; ACTIVATION; CANCER; SURVIVAL; IL-6; RECEPTORS; HETEROGENEITY; INFLAMMATION; EXPRESSION; INDUCTION;

D O I：

10.1093/brain/aws028

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

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.

引用

页码：1055 / 1069

页数：15

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