Department of Neurosurgery and Department of Neuroscience, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine, Xiamen University, Xiamen, Fujian, China.
Cell Death Dis. 2024 Oct 1;15(10):722. doi: 10.1038/s41419-024-07094-7.
CD2-associated protein (CD2AP) is a scaffolding/adaptive protein that regulates intercellular adhesion and multiple signaling pathways. Although emerging evidence suggests that CD2AP is associated with several malignant tumors, there is no study investigating the expression and biological significance of CD2AP in glioblastoma multiforme (GBM). Here by studying public datasets, we found that CD2AP expression was significantly elevated in GBM and that glioma patients with increased CD2AP expression had a worse prognosis. We also confirmed the increase of CD2AP expression in clinical GBM samples and GBM cell lines. CD2AP overexpression in GBM cells promoted their proliferation, colony formation, migration, and invasion in vitro and their tumorigenesis in vivo, and reduced cell apoptosis both at basal levels and in response to temozolomide. While CD2AP knockdown had the opposite effects. Mechanistically, we revealed that CD2AP interacted with TRIM5, an NF-κB modulator. CD2AP overexpression and knockdown increased and decreased TRIM5 levels as well as the NF-κB activity, respectively. Moreover, downregulation of TRIM5 reversed elevated NF-κB activity in GBM cells with CD2AP overexpression; and inhibition of the NF-κB activity attenuated malignant features of GBM cells with CD2AP overexpression. Our findings demonstrate that CD2AP promotes GBM progression through activating TRIM5-mediated NF-κB signaling and that downregulation of CD2AP can attenuate GBM malignancy, suggesting that CD2AP may become a biomarker and the CD2AP-TRIM5-NF-κB axis may become a therapeutic target for GBM.
CD2 相关蛋白（CD2AP）是一种支架/适应性蛋白，可调节细胞间黏附及多种信号通路。尽管有新的证据表明 CD2AP 与多种恶性肿瘤有关，但目前尚无研究调查 CD2AP 在多形性胶质母细胞瘤（GBM）中的表达及其生物学意义。在这里，通过研究公共数据集，我们发现 CD2AP 在 GBM 中表达显著上调，且 CD2AP 表达增加的胶质瘤患者预后更差。我们还在临床 GBM 样本和 GBM 细胞系中证实了 CD2AP 表达的增加。在 GBM 细胞中过表达 CD2AP 可促进其在体外的增殖、集落形成、迁移和侵袭，以及体内的致瘤性，并且在基础水平和对替莫唑胺的反应中均减少细胞凋亡。而 CD2AP 敲低则具有相反的作用。从机制上讲，我们揭示了 CD2AP 与 TRIM5 相互作用，TRIM5 是一种 NF-κB 调节剂。CD2AP 过表达和敲低分别增加和降低了 TRIM5 水平以及 NF-κB 活性。此外，下调 TRIM5 可逆转 GBM 细胞中 CD2AP 过表达引起的 NF-κB 活性升高；并且抑制 NF-κB 活性可减弱 CD2AP 过表达的 GBM 细胞的恶性特征。我们的研究结果表明，CD2AP 通过激活 TRIM5 介导的 NF-κB 信号促进 GBM 进展，而下调 CD2AP 可减弱 GBM 的恶性程度，提示 CD2AP 可能成为一种生物标志物，CD2AP-TRIM5-NF-κB 轴可能成为 GBM 的治疗靶点。
