胶质母细胞瘤 (GB) 被认为是最具侵袭性的脑肿瘤之一，中位生存期为 14.6 个月。然而，仍有一些患者的生存时间超过3年，这种临床现象背后的生物学原因引起了我们的研究兴趣。通过对从存活超过 3 年的 GB 患者与存活不到 1 年的患者获得的肿瘤组织进行蛋白质组学分析，我们发现存活时间较短的患者中 SelK 显着上调。因此，我们推测SelK可能是与GBM发生和进展相关的重要指标。通过对GB患者的蛋白质组学和免疫组化分析，探讨SelK与临床预后的相关性。通过细胞周期分析、细胞活力测定和异种移植模型评估细胞表型。进行免疫印迹和免疫共沉淀来验证 SelK 介导的 CDK4 泛素依赖性降解。发现与长期幸存者（≥3 年）相比，短期幸存者（≤1 年）的 GB 样本中的 SelK 显着上调年），其表达水平与临床预后呈负相关。 SelK表达的敲低会降低GB细胞的活力，诱导G0/G1期停滞，并损害裸鼠移植神经胶质瘤细胞的生长。 SelK 诱导的 ER 应激下调会导致 SKP2 表达减少和 β-TrCP1 表达上调。上调β-TrCP1，从而加速CDK4的泛素依赖性降解，最终抑制GB细胞的恶性增殖。本研究发现预后不良的GB患者中SelK表达显着增加，揭示SelK与GB细胞呈负相关表达和患者结果。进一步的机制研究表明，SelK 通过靶向内质网应激/SKP2/β-TrCP1/CDK4 轴来增强 GB 细胞的增殖。© 2024。作者。

Glioblastoma (GB) is recognized as one of the most aggressive brain tumors, with a median survival of 14.6 months. However, there are still some patients whose survival time was greater than 3 years, and the biological reasons behind this clinical phenomenon arouse our research interests. By conducting proteomic analysis on tumor tissues obtained from GB patients who survived over 3 years compared to those who survived less than 1 year, we identified a significant upregulation of SelK in patients with shorter survival times. Therefore, we hypothesized that SelK may be an important indicator related to the occurrence and progression of GBM.Proteomics and immunohistochemistry from GB patients were analyzed to investigate the correlation between SelK and clinical prognosis. Cellular phenotypes were evaluated by cell cycle analysis, cell viability assays, and xenograft models. Immunoblots and co-immunoprecipitation were conducted to verify SelK-mediated ubiquitin-dependent degradation of CDK4.SelK was found to be significantly upregulated in GB samples from short-term survivors (≤ 1 year) compared to those from long-term survivors (≥ 3 years), and its expression levels were negatively correlated with clinical prognosis. Knocking down of SelK expression reduced GB cell viability, induced G0/G1 phase arrest, and impaired the growth of transplanted glioma cells in nude mice. Down-regulation of SelK-induced ER stress leads to a reduction in the expression of SKP2 and an up-regulation of β-TrCP1 expression. Up-regulation of β-TrCP1, thereby accelerating the ubiquitin-dependent degradation of CDK4 and ultimately inhibiting the malignant proliferation of the GB cells.This study discovered a significant increase in SelK expression in GB patients with poor prognosis, revealing a negative correlation between SelK expression and patient outcomes. Further mechanistic investigations revealed that SelK enhances the proliferation of GB cells by targeting the endoplasmic reticulum stress/SKP2/β-TrCP1/CDK4 axis.© 2024. The Author(s).