Gao Yang, Zheng Hui, Li Liangdong, Feng Mingtao, Chen Xin, Hao Bin, Lv Zhongwei, Zhou Xiaoyan, Cao Yiqun
Department of Neurosurgery, Fudan University Shanghai Cancer Center, Shanghai, China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Front Cell Dev Biol. 2021 Mar 4;9:598377. doi: 10.3389/fcell.2021.598377. eCollection 2021.
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 prostate-specific membrane antigen (PSMA) in angiogenesis, this study aims to explore the functions of PSMA in GBM.
Clinical 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 experiment had been also conducted.
We 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 growth of GBM could be alleviated by the treatment of 2-PMPA.
This study identified PSMA as a critical regulator in angiogenesis and progression of GBM, which might be a promising therapeutic target for GBM treatment.
多形性胶质母细胞瘤（GBM）是中枢神经系统（CNS）最常见的原发性恶性肿瘤，预后极差。结合血管生成在肿瘤进展中的作用以及前列腺特异性膜抗原（PSMA）在血管生成中的作用，本研究旨在探讨PSMA在GBM中的功能。
收集2018年1月至2019年6月在复旦大学附属上海肿瘤医院接受手术治疗的60例GBM临床标本。采用免疫组织化学染色检测GBM组织中PSMA和CD31的表达。通过生物信息学评估PSMA的预后意义。将转染PSMA过表达质粒的人脐静脉内皮细胞（HUVECs）或用基于GBM细胞收集的条件培养基培养的细胞用于CCK8、Transwell和管形成试验。采用高通量测序和免疫沉淀法探讨其潜在机制。此外，还进行了实验。
我们发现PSMA在GBM组织血管内皮中大量表达，而在正常组织血管中不表达，这与预后不良显著相关。PSMA过表达可促进人脐静脉内皮细胞（HUVECs）的增殖、侵袭和管形成能力。此外，U87或U251条件培养基可上调PSMA表达并对HUVECs的表型产生类似影响，而2-PMPA处理可部分减弱所有这些影响。机制研究表明，PSMA可能通过与整合素β4（ITGB4）相互作用并激活NF-κB信号通路促进GBM的血管生成。2-PMPA治疗可减轻GBM的生长。
本研究确定PSMA是GBM血管生成和进展的关键调节因子，可能是GBM治疗的一个有前景的治疗靶点。
