SelK通过抑制β-TrCP1介导的CDK4泛素依赖性降解,促进胶质母细胞瘤细胞增殖。

IF 11.4 1区 医学 Q1 ONCOLOGY Journal of Experimental & Clinical Cancer Research Pub Date : 2024-08-19 DOI:10.1186/s13046-024-03157-x
Jizhen Li, Lingling Zhao, Zerui Wu, Shirui Huang, Junyu Wang, Yuanyuan Chang, Li Liu, Honglei Jin, Jianglong Lu, Chuanshu Huang, Qipeng Xie, Haishan Huang, Zhipeng Su
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引用次数: 0

摘要

背景:胶质母细胞瘤(GB)是公认的侵袭性最强的脑肿瘤之一,中位生存期为 14.6 个月。然而,仍有一些患者的生存期超过 3 年,这一临床现象背后的生物学原因引起了我们的研究兴趣。通过对存活时间超过 3 年的 GB 患者与存活时间不足 1 年的患者的肿瘤组织进行蛋白质组学分析,我们发现在存活时间较短的患者中,SelK 有明显的上调。因此,我们推测SelK可能是与GBM的发生和发展相关的一个重要指标:方法:对GB患者的蛋白质组学和免疫组化进行分析,研究SelK与临床预后的相关性。细胞表型通过细胞周期分析、细胞活力测定和异种移植模型进行评估。通过免疫印迹和共免疫沉淀来验证SelK介导的泛素依赖性CDK4降解:结果:与长期存活者(≥3年)相比,SelK在短期存活者(≤1年)的GB样本中明显上调,其表达水平与临床预后呈负相关。敲除SelK的表达可降低GB细胞的存活率,诱导G0/G1期停滞,并损害裸鼠移植胶质瘤细胞的生长。SelK诱导的ER应激的下调导致SKP2表达的减少和β-TrCP1表达的上调。β-TrCP1的上调,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,在预后不良的GB患者中,SelK的表达明显增加,揭示了SelK表达与患者预后之间的负相关。进一步的机理研究发现,SelK通过靶向内质网应激/SKP2/β-TrCP1/CDK4轴来增强GB细胞的增殖。
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SelK promotes glioblastoma cell proliferation by inhibiting β-TrCP1 mediated ubiquitin-dependent degradation of CDK4.

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

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来源期刊
CiteScore
18.20
自引率
1.80%
发文量
333
审稿时长
1 months
期刊介绍: The Journal of Experimental & Clinical Cancer Research is an esteemed peer-reviewed publication that focuses on cancer research, encompassing everything from fundamental discoveries to practical applications. We welcome submissions that showcase groundbreaking advancements in the field of cancer research, especially those that bridge the gap between laboratory findings and clinical implementation. Our goal is to foster a deeper understanding of cancer, improve prevention and detection strategies, facilitate accurate diagnosis, and enhance treatment options. We are particularly interested in manuscripts that shed light on the mechanisms behind the development and progression of cancer, including metastasis. Additionally, we encourage submissions that explore molecular alterations or biomarkers that can help predict the efficacy of different treatments or identify drug resistance. Translational research related to targeted therapies, personalized medicine, tumor immunotherapy, and innovative approaches applicable to clinical investigations are also of great interest to us. We provide a platform for the dissemination of large-scale molecular characterizations of human tumors and encourage researchers to share their insights, discoveries, and methodologies with the wider scientific community. By publishing high-quality research articles, reviews, and commentaries, the Journal of Experimental & Clinical Cancer Research strives to contribute to the continuous improvement of cancer care and make a meaningful impact on patients' lives.
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