Department of Clinical Laboratory, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, No.109, Xueyuan West Road, Lucheng District, Wenzhou, 325027, Zhejiang, China.
Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Chashan, Wenzhou, 325035, Zhejiang, China.
J Exp Clin Cancer Res. 2024 Aug 19;43(1):231. doi: 10.1186/s13046-024-03157-x.
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.
胶质母细胞瘤（GB）是一种侵袭性很强的脑肿瘤，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。通过对生存时间超过 3 年和生存时间不到 1 年的 GB 患者肿瘤组织进行蛋白质组学分析，我们发现短生存期患者 SelK 的表达显著上调。因此，我们假设 SelK 可能是与 GBM 发生和进展相关的重要指标。
分析了 GB 患者的蛋白质组学和免疫组织化学数据，以研究 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。通过免疫印迹和共免疫沉淀验证 SelK 介导的 CDK4 泛素依赖性降解。
与长期生存者（≥3 年）相比，短期生存者（≤1 年）的 GB 样本中 SelK 表达显著上调，其表达水平与临床预后呈负相关。敲低 SelK 表达可降低 GB 细胞活力，诱导 G0/G1 期阻滞，并抑制裸鼠移植的神经胶质瘤细胞生长。SelK 下调诱导内质网应激导致 SKP2 表达减少和 β-TrCP1 表达上调。β-TrCP1 的上调加速了 CDK4 的泛素依赖性降解，最终抑制了 GB 细胞的恶性增殖。
本研究发现预后不良的 GB 患者 SelK 表达显著增加，揭示了 SelK 表达与患者结局之间的负相关。进一步的机制研究表明，SelK 通过靶向内质网应激/SKP2/β-TrCP1/CDK4 轴增强了 GB 细胞的增殖。
