Bmi-1 Promotes Glioma Angiogenesis by Activating NF-κB Signaling

Lili Jiang,Shi-Yuan Cheng,Mengfeng Li,Libing Song,Yi Yang,Jueheng Wu,Bo Hu,Xun Zhu,Guillermo Velasco

doi:10.1371/journal.pone.0055527

Abstract

Angiogenesis in glioma is associated with the poor prognosis of the disease and closely correlates with the highly invasive phenotype of glioma cells, which represents the most challenging impediment against the currently glioma treatments. Bmi-1, an onco-protein, has been implicated in the progression of various human cancers, including gliomas, whereas its role in glioma angiogenesis remains unclear. Our current study examined the effects of Bmi-1 on glioma angiogenesis in vitro as well as in vivo. We found that overexpression of Bmi-1 enhanced, whereas knockdown of Bmi-1 diminished, the capability of glioma cells to induce tubule formation and migration of endothelial cells and neovascularization in chicken chorioallantoic membrane. In vivo, Bmi-1 overexpression and knockdown, respectively, promoted and inhibited angiogenesis in orthotopically transplanted human gliomas. Furthermore, NF-κB activity and VEGF-C expression was induced by Bmi-1 overexpression, whereas Bmi-1 knockdown attenuated NF-κB signaling and decreased VEGF-C expression. Additionally suppression of NF-κB activity using a specific chemical inhibitor abrogated the NF-κB activation and the pro-angiogenic activities of glioma cells. Together, our data suggest that Bmi-1 plays an important role in glioma angiogenesis and therefore could represent a potential target for anti-angiogenic therapy against the disease.

Highlights

Angiogenesis, the formation of new blood vessels from preexisting ones, occurs in many physiological and pathological conditions such as development, wound healing and cancer [1]
Toward an understanding of the mechanism by which Bmi-1 promotes the angiogenesis of glioma cells, we investigated whether Bmi-1 induces the expression vascular epithelial growth factors (VEGF)-C in glioma cells
The major finding of this study is that upregulated Bmi-1 promotes angiogenesis in human gliomas in vitro and in vivo

Summary

Introduction

Angiogenesis, the formation of new blood vessels from preexisting ones, occurs in many physiological and pathological conditions such as development, wound healing and cancer [1]. Tumor cells produce angiogenesis inducers, represented by vascular epithelial growth factors (VEGF), which play a crucial role in endothelial survival, proliferation and differentiation, as well as new vessel sprouting [3]. Malignant gliomas, such as glioblastoma multiforme (GBM), are characterized by highly aggressive phenotypes, including prominent vascularization underlied by upregulation of pro-angiogenic factors and endothelial proliferation [8]. In this context, the poor patient survival is largely attributable to the high invasiveness and accelerated growth of the tumor [9]. Understanding the molecular mechanisms mediating the development and progression of glioma angiogenesis will help identify diagnostic/prognostic biomarkers as well as therapeutic targets against the deadly condition

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Conclusion