Neuropilin-1 enhances temozolomide resistance in glioblastoma via the STAT1/p53/p21 axis.

IF 1.3 4区医学 Q4 CLINICAL NEUROLOGY

Neuropathology Pub Date : 2024-08-01 Epub Date: 2024-03-06 DOI:10.1111/neup.12966

Ping Huang, Lixia Zhang, Hongwei Wang, Changwu Dou, Haitao Ju, Peng Yue, Jiaxing Ren

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Abstract

Glioblastoma (GBM) is the most prevalent primary intracranial tumor. Temozolomide (TMZ) is the first-line chemotherapy for GBM. Nonetheless, the development of TMZ resistance has become a main cause of treatment failure in GBM patients. Evidence suggests that neuropilin-1 (NRP-1) silencing can attenuate GBM cell resistance to TMZ. This study aims to determine potential mechanisms by which NRP-1 affects TMZ resistance in GBM. The parental U251 and LN229 GBM cells were exposed to increasing concentrations of TMZ to construct TMZ-resistant GBM cells (U251/TMZ, LN229/TMZ). BALB/c nude mice were injected with U251/TMZ cells to establish the xenograft mouse model. Functional experiments were carried out to examine NRP-1 functions. Western blotting and real-time quantitative polymerase chain reaction were used to evaluate molecular protein and mRNA expression, respectively. Immunohistochemical staining showed NRP-1 and STAT1 expression in mouse tumors. The results showed that NRP-1 was highly expressed in TMZ-resistant cells. Moreover, knocking down NRP-1 attenuated the TMZ resistance of U251/TMZ cells, while upregulating NRP-1 enhanced TMZ resistance of the parental cells. NRP-1 silencing elevated GBM cell sensitivity to TMZ in tumor-bearing mice. Depleting NRP-1 reduced STAT1, p53, and p21 expression in U251/TMZ cells. STAT1 depletion offset NRP-1 silencing evoked attenuation of GBM cell resistance to TMZ. Collectively, our study reveals that NRP-1 enhances TMZ resistance in GBM possibly by regulating the STAT1/p53/p21 axis.

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神经蛋白-1通过STAT1/p53/p21轴增强胶质母细胞瘤对替莫唑胺的耐药性

胶质母细胞瘤（GBM）是最常见的原发性颅内肿瘤。替莫唑胺（TMZ）是治疗 GBM 的一线化疗药物。然而，TMZ 耐药性的产生已成为 GBM 患者治疗失败的主要原因。有证据表明，沉默神经蛋白1（NRP-1）可减轻GBM细胞对TMZ的耐药性。本研究旨在确定 NRP-1 影响 GBM 细胞 TMZ 耐药性的潜在机制。将亲本 U251 和 LN229 GBM 细胞暴露于浓度不断增加的 TMZ，以构建 TMZ 抗性 GBM 细胞（U251/TMZ、LN229/TMZ）。给 BALB/c 裸鼠注射 U251/TMZ 细胞，建立异种移植小鼠模型。进行了功能实验以检测 NRP-1 的功能。分别使用 Western 印迹和实时定量聚合酶链反应评估分子蛋白和 mRNA 的表达。免疫组化染色显示了小鼠肿瘤中 NRP-1 和 STAT1 的表达。结果显示，NRP-1在TMZ耐药细胞中高表达。此外，敲除NRP-1可减轻U251/TMZ细胞对TMZ的耐药性，而上调NRP-1可增强亲代细胞对TMZ的耐药性。在肿瘤小鼠体内，沉默NRP-1可提高GBM细胞对TMZ的敏感性。消耗 NRP-1 可减少 U251/TMZ 细胞中 STAT1、p53 和 p21 的表达。STAT1 的消耗抵消了 NRP-1 的沉默，从而削弱了 GBM 细胞对 TMZ 的耐药性。总之，我们的研究揭示了NRP-1可能通过调节STAT1/p53/p21轴增强了GBM对TMZ的耐药性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Neuropathology 医学-病理学

CiteScore

4.10

自引率

4.30%

发文量

105

审稿时长

6-12 weeks

期刊介绍： Neuropathology is an international journal sponsored by the Japanese Society of Neuropathology and publishes peer-reviewed original papers dealing with all aspects of human and experimental neuropathology and related fields of research. The Journal aims to promote the international exchange of results and encourages authors from all countries to submit papers in the following categories: Original Articles, Case Reports, Short Communications, Occasional Reviews, Editorials and Letters to the Editor. All articles are peer-reviewed by at least two researchers expert in the field of the submitted paper.