Wu HaoYuan, Yang ZhiHao, Chang ChenXi, Wang ZhiWei, Zhang DeRan, Guo QingGuo, Zhao Bing
Department of Neurosurgery, The Second Affiliated Hospital of Anhui Medical University, Anhui Medical University, 678 Fu Rong Road, Hefei, Anhui Province, 230601, China.
Cancer Cell Int. 2024 May 11;24(1):168. doi: 10.1186/s12935-024-03358-6.
"Disulfide death," a form of cellular demise, is triggered by the abnormal accumulation of intracellular disulfides under conditions of glucose deprivation. However, its role in the prognosis of glioma remains undetermined. Therefore, the main objective of this study is to establish prognostic signature based on disulfide death-related genes (DDRGs) and to provide new solutions in choosing the effective treatment of glioma.
The RNA transcriptome, clinical information, and mutation data of glioma samples were sourced from The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA), while normal samples were obtained from the Genotype-Tissue Expression (GTEx). DDRGs were compiled from previous studies and selected through differential analysis and univariate Cox regression analysis. The molecular subtypes were determined through consensus clustering analysis. Further, LASSO analysis was employed to select characteristic genes, and subsequently, a risk model comprising seven DDRGs was constructed based on multivariable Cox analysis. Kaplan-Meier survival curves were employed to assess survival differences between high and low-risk groups. Additionally, functional analyses (GO, KEGG, GSEA) were conducted to explore the potential biological functions and signaling pathways of genes associated with the model. The study also explored immune checkpoint (ICP) genes, immune cell infiltration levels, and immune stromal scores. Finally, the effect of Importin-4(IPO4) on glioma has been further confirmed through RT-qPCR, Western blot, and cell functional experiments.
7 genes associated with disulfide death were obtained and two subgroups of patients with different prognosis and clinical characteristics were identified. Risk signature was subsequently developed and proved to serve as an prognostic predictor. Notably, the high-risk group exhibited an immunosuppressive microenvironment characterized by a high concentration of M2 macrophages and regulatory T cells (Tregs). In contrast, the low-risk group showed lower half-maximal inhibitory concentration (IC50) values. Therefore, patients in the high-risk group may benefit more from immunotherapy, while patients in the low-risk group may benefit more from chemotherapy. In addition, in vitro experiments have shown that inhibition of the expression of IPO4 leads to a significant reduction in the proliferation, migration, and invasion of glioma cells.
This study identified two glioma subtypes and constructed a prognostic signature based on DDRGs. The signature has the potential to optimize the selection of patients for immune- and chemotherapy and provided a potential therapeutic target for glioma.
“二硫键死亡”是一种细胞死亡形式，由葡萄糖剥夺条件下细胞内二硫键的异常积累引发。然而，其在胶质瘤预后中的作用仍未确定。因此，本研究的主要目的是基于二硫键死亡相关基因（DDRGs）建立预后特征，并为选择有效的胶质瘤治疗方法提供新的解决方案。
胶质瘤样本的RNA转录组、临床信息和突变数据来自癌症基因组图谱（TCGA）和中国胶质瘤基因组图谱（CGGA），而正常样本则取自基因型-组织表达（GTEx）。DDRGs是根据先前的研究汇编而成，并通过差异分析和单变量Cox回归分析进行筛选。通过一致性聚类分析确定分子亚型。此外，采用LASSO分析选择特征基因，随后基于多变量Cox分析构建了一个包含7个DDRGs的风险模型。采用Kaplan-Meier生存曲线评估高风险组和低风险组之间的生存差异。此外，进行了功能分析（GO、KEGG、GSEA）以探索与该模型相关基因的潜在生物学功能和信号通路。该研究还探讨了免疫检查点（ICP）基因、免疫细胞浸润水平和免疫基质评分。最后，通过RT-qPCR、蛋白质免疫印迹和细胞功能实验进一步证实了输入蛋白4（IPO4）对胶质瘤的影响。
获得了7个与二硫键死亡相关的基因，并鉴定出了两个具有不同预后和临床特征的患者亚组。随后开发了风险特征，并证明其可作为预后预测指标。值得注意的是，高风险组表现出以高浓度M2巨噬细胞和调节性T细胞（Tregs）为特征的免疫抑制微环境。相比之下，低风险组的半数最大抑制浓度（IC50）值较低。因此，高风险组的患者可能从免疫治疗中获益更多，而低风险组的患者可能从化疗中获益更多。此外，体外实验表明，抑制IPO4的表达会导致胶质瘤细胞的增殖、迁移和侵袭显著减少。
本研究鉴定了两种胶质瘤亚型，并基于DDRGs构建了预后特征模型。该特征模型有可能优化免疫治疗和化疗患者的选择，并为胶质瘤提供潜在的治疗靶点。
