BMAL1 may be involved in angiogenesis and peritumoral cerebral edema of human glioma by regulating VEGF and ANG2.

Fan Wang,Lvan Chen,Ling Zhu,Caiyan Li,Fei Han

doi:10.18632/aging.203708

Abstract

The rhythm gene BMAL1 (Brain and Muscle ARNT-Like 1) may play an important role in glioma tolerance for anti-angiogenesis therapy. In humans with glioma of different pathological grades, BMAL1 expression was significantly different, and the expression of ANG2 (Angiopoietin 2) and VEGF (Vascular endothelial growth factor) was positively correlated with the expression of BMAL1. Additionally, BMAL1 expression is positively correlated with the microvascular density and peritumoral edema of glioma. According to in vitro experiments, silencing the expression of BMAL1 in primary glioma cells results in a decrease in the expression of VEGF. In contrast, overexpression of BMAL1 promotes the expression of ANG2 and VEGF via HIF-1a pathway. Therefore, BMAL1 likely participates in the angiogenesis of glioma by modulating ANG2 and VEGF expression, alters the therapeutic effect of anti-angiogenic treatments, and promotes peritumoral brain edema of glioma.

Highlights

Glioma is the most common malignancy of the central nervous system, and it is highly invasive, results in a poor prognosis, and is prone to recurrence after surgery
BMAL1 was expressed at different levels in both glioma and normal tissues, and all the staining was observed in the nucleus (Figure 1)
ANG1, ANG2 and VEGF are expressed at high levels in gliomas, and significant differences in their expression were observed in different pathological grades

Summary

Introduction

Glioma is the most common malignancy of the central nervous system, and it is highly invasive, results in a poor prognosis, and is prone to recurrence after surgery. Conventional treatment for glioblastoma involves extensive radical resection combined with adjuvant radiotherapy and chemotherapy, the one-year cumulative survival rate of patients is still less than 30%. Vascular therapy targeting active angiogenic factors has become the standard treatment for some tumors, including colon cancer and kidney cancer [2, 3], and an adjuvant therapy for glioma [4, 5]. In addition to the limitations of the drug itself, the most important limitation is the drug resistance of tumor cells [8, 9]. This tolerance may be related to rhythm genes [10]

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Conclusion