Abstract
BackgroundGlioblastoma multiforme (GBM) is the most common primary malignant tumor in the central nervous system (CNS), causing the extremely poor prognosis. Combining the role of angiogenesis in tumor progression and the role of prostate-specific membrane antigen (PSMA) in angiogenesis, this study aims to explore the functions of PSMA in GBM.MethodsClinical GBM specimens were collected from 60 patients who accepted surgical treatment in Fudan University Shanghai Cancer Center between January 2018 and June 2019. Immunohistochemical staining was used to detect PSMA and CD31 expression in GBM tissues. Prognostic significance of PSMA was evaluated by bioinformatics. Human umbilical vein endothelial cells (HUVECs) transfected with PSMA overexpression plasmids or cultured with conditioned medium collected based on GBM cells, were used for CCK8, Transwell and tube formation assays. High-throughput sequencing and immunoprecipitation were used to explore the underlying mechanism. Furthermore, the in vivo experiment had been also conducted.ResultsWe demonstrated that PSMA was abundantly expressed in endothelium of vessels of GBM tissues but not in vessels of normal tissues, which was significantly correlated with poor prognosis. Overexpression of PSMA could promotes proliferation, invasion and tube formation ability of human umbilical vein endothelial cells (HUVECs). Moreover, U87 or U251 conditioned medium could upregulated PSMA expression and induce similar effects on phenotypes of HUVECs, all of which could be partially attenuated by 2-PMPA treatment. The mechanistic study revealed that PSMA might promote angiogenesis of GBM through interacting with Integrin β4 (ITGB4) and activating NF-κB signaling pathway. The in vivo growth of GBM could be alleviated by the treatment of 2-PMPA.ConclusionThis study identified PSMA as a critical regulator in angiogenesis and progression of GBM, which might be a promising therapeutic target for GBM treatment.
Highlights
Glioma is the most common primary central nervous system (CNS) tumor, accounting for about 40–50% of intracranial tumors
The results demonstrated that the expression level and localization of prostatespecific membrane antigen (PSMA) in Glioblastoma multiforme (GBM) tissue was consistent with CD31, indicating the potential role of PSMA in angiogenesis of GBM (Figure 1B)
The results showed that PSMA could enhance the aggressiveness of HUVEC cells by promoting the activities of integrin β1 and PAK (p21-activated kinase)-1, thereby affecting angiogenesis
Summary
Glioma is the most common primary central nervous system (CNS) tumor, accounting for about 40–50% of intracranial tumors. Glioblastoma multiforme (GBM) is the most aggressive type of glioma in the CNS (Gusyatiner and Hegi, 2018). It is extremely urgent to explore novel therapeutic targets to improve the overall survival of glioma patients. Researchers have found that GBM is one of the most vascularrich malignant tumors, and the aggressive nature of GBM is closely related with tumor angiogenesis (Touat et al, 2017). Glioblastoma multiforme (GBM) is the most common primary malignant tumor in the central nervous system (CNS), causing the extremely poor prognosis. Combining the role of angiogenesis in tumor progression and the role of prostatespecific membrane antigen (PSMA) in angiogenesis, this study aims to explore the functions of PSMA in GBM
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