基于线粒体和氧化应激相关基因的胶质母细胞瘤新型预后标志物的鉴定和验证。
Identification and validation of a novel prognostic signature based on mitochondria and oxidative stress related genes for glioblastoma.
机构信息
Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China.
Department of Endocrinology & Metabolism, Renmin Hospital of Wuhan University, Wuhan, China.
出版信息
J Transl Med. 2023 Feb 22;21(1):136. doi: 10.1186/s12967-023-03970-6.
BACKGROUND
Mitochondria represent a major source of reactive oxygen species (ROS) in cells, and the direct increase in ROS content is the primary cause of oxidative stress, which plays an important role in tumor proliferation, invasion, angiogenesis, and treatment. However, the relationship between mitochondrial oxidative stress-related genes and glioblastoma (GBM) remains unclear. This study aimed to investigate the value of mitochondria and oxidative stress-related genes in the prognosis and therapeutic targets of GBM.
METHODS
We retrieved mitochondria and oxidative stress-related genes from several public databases. The LASSO regression and Cox analyses were utilized to build a risk model and the ROC curve was used to assess its performance. Then, we analyzed the correlation between the model and immunity and mutation. Furthermore, CCK8 and EdU assays were utilized to verify the proliferative capacity of GBM cells and flow cytometry was used to analyze apoptosis rates. Finally, the JC-1 assay and ATP levels were utilized to detect mitochondrial function, and the intracellular ROS levels were determined using MitoSOX and BODIPY 581/591 C11.
RESULTS
5 mitochondrial oxidative stress-related genes (CTSL, TXNRD2, NUDT1, STOX1, CYP2E1) were screened by differential expression analysis and Cox analysis and incorporated in a risk model which yielded a strong prediction accuracy (AUC value = 0.967). Furthermore, this model was strongly related to immune cell infiltration and mutation status and could identify potential targeted therapeutic drugs for GBM. Finally, we selected NUDT1 for further validation in vitro. The results showed that NUDT1 was elevated in GBM, and knockdown of NUDT1 inhibited the proliferation and induced apoptosis of GBM cells, while knockdown of NUDT1 damaged mitochondrial homeostasis and induced oxidative stress in GBM cells.
CONCLUSION
Our study was the first to propose a prognostic model of mitochondria and oxidative stress-related genes, which provided potential therapeutic strategies for GBM patients.
背景
线粒体是细胞中活性氧（ROS）的主要来源，ROS 含量的直接增加是氧化应激的主要原因，氧化应激在肿瘤增殖、侵袭、血管生成和治疗中起着重要作用。然而，线粒体氧化应激相关基因与胶质母细胞瘤（GBM）之间的关系尚不清楚。本研究旨在探讨线粒体和氧化应激相关基因在 GBM 预后和治疗靶点中的价值。
方法
我们从多个公共数据库中检索到线粒体和氧化应激相关基因。利用 LASSO 回归和 Cox 分析构建风险模型，并通过 ROC 曲线评估其性能。然后，我们分析了模型与免疫和突变的相关性。此外，我们还利用 CCK8 和 EdU 测定法验证了 GBM 细胞的增殖能力，并用流式细胞术分析了细胞凋亡率。最后，我们利用 JC-1 测定法和 ATP 水平检测线粒体功能，并用 MitoSOX 和 BODIPY 581/591 C11 测定细胞内 ROS 水平。
结果
通过差异表达分析和 Cox 分析筛选出 5 个线粒体氧化应激相关基因（CTSL、TXNRD2、NUDT1、STOX1、CYP2E1），并纳入风险模型，该模型具有很强的预测准确性（AUC 值=0.967）。此外，该模型与免疫细胞浸润和突变状态密切相关，能够识别 GBM 的潜在靶向治疗药物。最后，我们选择 NUDT1 进行进一步的体外验证。结果表明，NUDT1 在 GBM 中上调，敲低 NUDT1 抑制 GBM 细胞的增殖并诱导其凋亡，而敲低 NUDT1 破坏了 GBM 细胞中线粒体的动态平衡并诱导其氧化应激。
结论
本研究首次提出了线粒体和氧化应激相关基因的预后模型，为 GBM 患者提供了潜在的治疗策略。
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