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Published on: November 28, 2015
Glioblastoma-associated microglia-derived exosomal circKIF18A promotes angiogenesis by targeting FOXC2
Yang Jiang1, Junshuang Zhao2, Jinkun Xu2
1Department of Neurosurgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China.
Abstract:
Glioblastoma multiforme (GBM) is the most lethal primary tumor with active neovascularization in the central nervous system. Studying the novel molecular mechanisms of GBM angiogenesis is very important. The glioblastoma-associated microglia (GAM) M2 polarization was constructed, and microglia-derived exosomes (MDEs) were isolated to co-culture with human brain microvessel endothelial cells (hBMECs). CircRNA sequence and molecular biological experiments were used to detect the expression levels and regulation functions among circKIF18A, FOXC2, ITGB3, CXCR4, DLL4 and the PI3K/AKT signaling. The functional effects of silencing or overexpression of these molecules were evaluated in hBMECs viability, invasion, and tube formation in vitro and tumorigenicity in vivo. M2 microglia polarization is positively correlated with microvessels' density in GBM patients. M2 GAM can promote the angiogenesis of GBM via transporting exosomal circKIF18A into hBMECs. Mechanistically, circKIF18A can bind to, maintain the stability and nuclear translocation of FOXC2 in hBMECs. Furtherly, as a transcription factor, FOXC2 can directly bind to the promoter of ITGB3, CXCR4, and DLL4 and upregulate their expressions. Besides, FOXC2 can also activate the PI3K/AKT signaling and promote the angiogenesis of GBM. Our study identified a novel molecular mechanism for M2 GAM-derived exosomal circKIF18A participating in GBM angiogenesis via targeting FOXC2. This may provide a novel treatment target to improve the outcomes for anti-angiogenic therapies in GBM.
Insights
M2 glioblastoma-associated microglia promote brain tumor growth by sending exosomal circKIF18A to endothelial cells. This molecule activates FOXC2, driving angiogenesis and potentially offering new therapeutic targets for glioblastoma multiforme.
Area of Science:
- Neuro-oncology
- Molecular Biology
- Cancer Angiogenesis
Background:
- Glioblastoma multiforme (GBM) is a highly lethal brain tumor characterized by significant neovascularization.
- Understanding the molecular mechanisms of GBM angiogenesis is crucial for developing effective treatments.
- Glioblastoma-associated microglia (GAM) play a role in tumor progression, particularly M2-polarized microglia.
Purpose of the Study:
- To investigate the role of M2 GAM-derived exosomes in promoting GBM angiogenesis.
- To elucidate the molecular pathway involving circKIF18A, FOXC2, and downstream targets in GBM angiogenesis.
- To identify potential therapeutic targets for anti-angiogenic strategies in GBM.
Main Methods:
- Isolation of microglia-derived exosomes (MDEs) from M2-polarized GAM and co-culture with human brain microvessel endothelial cells (hBMECs).
- CircRNA sequencing and molecular biological experiments to analyze circKIF18A, FOXC2, ITGB3, CXCR4, DLL4, and PI3K/AKT signaling.
- In vitro (viability, invasion, tube formation) and in vivo (tumorigenicity) functional assays following gene silencing or overexpression.
Main Results:
- M2 GAM polarization positively correlates with microvessel density in GBM patients.
- Exosomal circKIF18A from M2 GAM promotes GBM angiogenesis by entering hBMECs.
- CircKIF18A stabilizes FOXC2, promoting its nuclear translocation, which then upregulates ITGB3, CXCR4, DLL4, and activates PI3K/AKT signaling.
Conclusions:
- A novel mechanism of M2 GAM-derived exosomal circKIF18A promoting GBM angiogenesis via the FOXC2/PI3K/AKT pathway is identified.
- This pathway represents a significant molecular mechanism contributing to GBM's aggressive neovascularization.
- Targeting this circKIF18A/FOXC2 axis offers a promising strategy for novel anti-angiogenic therapies in glioblastoma.
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