The miR-29 family members induce glioblastoma cell apoptosis by targeting cell division cycle 42 in a p53-dependent manner
The miR-29 family members induce glioblastoma cell apoptosis by targeting cell division cycle 42 in a p53-dependent manner
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miR-29家族成员通过p53依赖性方式靶向细胞分裂周期42诱导胶质母细胞瘤细胞凋亡
DOI：
10.1111/eci.13964
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Yu S
中科院分区：
文献类型：
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作者：
Shi C;Luo W;Sun C;Yu L;Zhou X;Hua D;Jiang Z;Wang Q;Yu S
背景新出现的证据表明 miR-29 是一种有前途的恶性肿瘤生物标志物和治疗靶点。 miR-29a/b/c在胶质瘤发病机制中的作用仍有待进一步研究。方法系统分析miR-29a/b/c和CDC42的表达水平，并通过Kaplan-Meier生存和Cox回归分析评估预后意义。通过碱性单细胞凝胶电泳测定、caspase 3/7 活性测定和蛋白质印迹法探讨 miR-29a/b/c 在细胞凋亡中的作用及其潜在机制。结果与 20 个非肿瘤对照脑组织相比，在我们的 147 例人胶质瘤标本中，随着 WHO 级别的升高，miR-29a/b/c 表达逐渐降低，并且 miR-29a/b/c 表达降低与更具侵袭性相关。表型。 Kaplan-Meier 和 Cox 回归分析表明，较低的 miR-29a/b/c 表达与较差的预后相关，这一点通过对 CGGA 队列中 198 名神经胶质瘤患者的分析得到证实。这些都表明miR-29a/b/c是神经胶质瘤患者预后的独立预测因子。 miR-29a/b/c 通过沉默 CDC42 诱导 GBM 细胞凋亡。进一步详细的机制研究表明，miR-29a/b/c 通过抑制 CDC42/PAK/AKT/MDM2 通路，以 p53 依赖性方式促进细胞凋亡。结论 miR-29a/b/c 是胶质瘤患者预后的独立预测因子。它们以 p53 依赖性方式通过沉默 CDC42 和抑制下游 PAK/AKT/MDM2 信号传导来诱导胶质母细胞瘤细胞凋亡。
BackgroundEmerging evidence has shown that miR‐29 is a promising biomarker and therapeutic target for malignancies. The roles of miR‐29a/b/c in glioma pathogenesis remain need further investigation.MethodsThe expression levels of miR‐29a/b/c and CDC42 were systematically analysed, and prognostic significance was evaluated by Kaplan–Meier survival and Cox regression analyses. The roles of miR‐29a/b/c in apoptosis and the underlying mechanisms were explored via an alkaline single‐cell gel electrophoresis assay, caspase 3/7 activity assays and Western blotting.ResultsmiR‐29a/b/c expression decreased progressively with the elevation of the WHO grade in our 147 human glioma specimens, compared with 20 non‐tumour control brain tissues, and decreased miR‐29a/b/c expression was associated with more aggressive phenotypes. Kaplan–Meier and Cox regression analyses demonstrated that lower miR‐29a/b/c expression was correlated with worse prognosis, which was confirmed by analysis of 198 glioma patients from the CGGA cohort. These all indicate that miR‐29a/b/c were independent predictors of prognosis in glioma patients. miR‐29a/b/c induced apoptosis in GBM cells by silencing CDC42. Further detailed mechanistic investigation revealed that miR‐29a/b/c promoted apoptosis in a p53‐dependent manner by suppressing the CDC42/PAK/AKT/MDM2 pathway.ConclusionsmiR‐29a/b/c are independent predictors of prognosis in glioma patients. They induce glioblastoma cell apoptosis via silencing of CDC42 and suppression of downstream PAK/AKT/MDM2 signalling in a p53‐dependent manner.