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半胱氨酸和甘氨酸丰富蛋白 2 通过作用于 Notch 信号级联反应对神经胶质瘤的恶性表型至关重要。

Cysteine and glycine-rich protein 2 is crucial for maintaining the malignant phenotypes of gliomas through its action on Notch signalling cascade.

机构信息

Department of Neurosurgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, No.32 West Second Section First Ring Road, Chengdu 610072, China.

Department of Neurosurgery, Second Affiliated Hospital of Xi'an Medical University, No. 167 Fangdong Street, Xi'an 710038, China.

出版信息

Toxicol Appl Pharmacol. 2024 Jun;487:116969. doi: 10.1016/j.taap.2024.116969. Epub 2024 May 12.

Abstract

Cysteine and glycine-rich protein 2 (CSRP2) is expressed differently in numerous cancers and plays a key role in carcinogenesis. However, the role of CSRP2 in glioma is unknown. This study sought to determine the expression profile and clinical significance of CSRP2 in glioma and explore its biological functions and mechanisms via lentivirus-mediated CSRP2 silencing experiments. Increased CSRP2 was frequently observed in gliomas, which was associated with clinicopathological characteristics and an unfavourable prognosis. Decreasing CSRP2 led to the suppression of malignant proliferation, metastasis and stemness in glioma cells while causing hypersensitivity to chemotherapeutic drugs. Mechanistic investigations revealed that CSRP2 plays a role in mediating the Notch signalling cascade. Silencing CSRP2 decreased the levels of Notch1, cleaved Notch1, HES1 and HEY1, suppressing the Notch signalling cascade. Reactivation of Notch markedly diminished the tumour-inhibiting effects of CSRP2 silencing on the malignant phenotypes of glioma cells. Notably, CSRP2-silencing glioma cells exhibited reduced potential in the formation of xenografts in nude mice in vivo, which was associated with an impaired Notch signalling cascade. These results showed that CSRP2 is overexpressed in glioma and has a crucial role in sustaining the malignant phenotypes of glioma, suggesting that targeting CSRP2 could be a promising strategy for glioma treatment.

摘要

富含半胱氨酸和甘氨酸蛋白 2(CSRP2)在许多癌症中表达不同,在致癌作用中发挥关键作用。然而,CSRP2 在神经胶质瘤中的作用尚不清楚。本研究旨在通过慢病毒介导的 CSRP2 沉默实验,确定 CSRP2 在神经胶质瘤中的表达谱和临床意义,并探讨其生物学功能和机制。CSRP2 在神经胶质瘤中频繁上调,与临床病理特征和不良预后相关。降低 CSRP2 导致神经胶质瘤细胞恶性增殖、转移和干性受到抑制,同时对化疗药物产生敏感性。机制研究表明,CSRP2 在介导 Notch 信号级联中发挥作用。沉默 CSRP2 降低了 Notch1、裂解 Notch1、HES1 和 HEY1 的水平,抑制了 Notch 信号级联。Notch 的重新激活显著减弱了 CSRP2 沉默对神经胶质瘤细胞恶性表型的肿瘤抑制作用。值得注意的是,CSRP2 沉默的神经胶质瘤细胞在体内裸鼠异种移植中形成肿瘤的潜能降低,这与 Notch 信号级联受损有关。这些结果表明,CSRP2 在神经胶质瘤中过度表达,在维持神经胶质瘤的恶性表型中起关键作用,表明靶向 CSRP2 可能是神经胶质瘤治疗的一种有前途的策略。

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