Role of Asparagine Endopeptidase in Mediating Wild-Type p53 Inactivation of Glioblastoma
Role of Asparagine Endopeptidase in Mediating Wild-Type p53 Inactivation of Glioblastoma
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天冬酰胺内肽酶在介导胶质母细胞瘤野生型 p53 失活中的作用
DOI：
10.1093/jnci/djz155
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发表时间：
2020-04-01
影响因子：
10.3
通讯作者：
Qiu, Yongming
中科院分区：
文献类型：
--
作者：
Lin, Yingying;Liao, Keman;Qiu, Yongming
背景资料：异柠檬酸脱氢酶野生型（WT）胶质母细胞瘤（GBM）占所有GBM的90%，但只有27%的异柠檬酸脱氢酶WT-GBM具有p53突变。然而，WT-p53在GBM中的肿瘤监视功能被颠覆的机制，不完全understood.Methods：我们研究了天冬酰胺酰内肽酶（AEP）的WT-p53蛋白水解失活及其对GBM进展的影响，在癌细胞，小鼠模型，和患者的标本，使用生化和功能测定。用酶联免疫吸附试验检测48例健康献血员和20例GBM患者血清中的IgG抗体。此外，在小鼠模型中评估了AEP抑制剂对GBM进展的影响（每组n = 6-8）。使用双尾Student t tests.Results：我们证明，AEP结合并直接切割WT-p53，导致抑制WT-p53介导的肿瘤抑制功能，在肿瘤细胞和基质细胞通过细胞外囊泡通信组之间的统计学意义。不可切割的p53-N311 A突变体的高表达拯救AEP诱导的肿瘤发生、增殖和抗凋亡能力。在小鼠模型中，AEP的敲低或药理学抑制减少了肿瘤发生并延长了存活期。但AEP过表达可促进肿瘤的发生，缩短生存期。此外，GBM组织中高AEP水平与GBM患者预后不良相关（n = 83;风险比= 3.94，95%置信区间= 1.87至8.28; P <0.001）。高血浆AEP水平和更大的肿瘤大小GBM患者（r = 0.6，P = .03），这显着降低后surgery.Conclusions：我们的研究结果表明，AEP促进GBM的进展，通过灭活WT-p53，并可能作为GBM的预后和治疗目标。
Background: Isocitrate dehydrogenase wild-type (WT) glioblastoma (GBM) accounts for 90% of all GBMs, yet only 27% of isocitrate dehydrogenase WT-GBMs have p53 mutations. However, the tumor surveillance function of WT-p53 in GBM is subverted by mechanisms that are not fully understood.Methods: We investigated the proteolytic inactivation of WT-p53 by asparaginyl endopeptidase (AEP) and its effects on GBM progression in cancer cells, murine models, and patients' specimens using biochemical and functional assays. The sera of healthy donors (n = 48) and GBM patients (n = 20) were examined by enzyme-linked immunosorbent assay. Furthermore, effects of AEP inhibitors on GBM progression were evaluated in murine models (n = 6-8 per group). The statistical significance between groups was determined using two-tailed Student t tests.Results: We demonstrate that AEP binds to and directly cleaves WT-p53, resulting in the inhibition of WT-p53-mediated tumor suppressor function in both tumor cells and stromal cells via extracellular vesicle communication. High expression of uncleavable p53-N311A-mutant rescue AEP-induced tumorigenesis, proliferation, and anti-apoptotic abilities. Knock down or pharmacological inhibition of AEP reduced tumorigenesis and prolonged survival in murine models. However, overexpression of AEP promoted tumorigenesis and shortened the survival time. Moreover, high AEP levels in GBM tissues were associated with a poor prognosis of GBM patients (n = 83; hazard ratio = 3.94, 95% confidence interval = 1.87 to 8.28; P < .001). A correlation was found between high plasma AEP levels and a larger tumor size in GBM patients (r = 0.6, P = .03), which decreased dramatically after surgery.Conclusions: Our results indicate that AEP promotes GBM progression via inactivation of WT-p53 and may serve as a prognostic and therapeutic target for GBM.