National Health Commission (NHC) Key Laboratory of Carcinogenesis, Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Front Immunol. 2023 Dec 15;14:1294459. doi: 10.3389/fimmu.2023.1294459. eCollection 2023.
Disulfidptosis, a newly defined type of programmed cell death, has emerged as a significant regulatory process in the development and advancement of malignant tumors, such as lower-grade glioma (LGG). Nevertheless, the precise biological mechanisms behind disulfidptosis in LGG are yet to be revealed, considering the limited research conducted in this field.
We obtained LGG data from the TCGA and CGGA databases and performed comprehensive weighted co-expression network analysis, single-sample gene set enrichment analysis, and transcriptome differential expression analyses. We discovered nine genes associated with disulfidptosis by employing machine learning methods like Cox regression, LASSO regression, and SVM-RFE. These were later used to build a predictive model for patients with LGG. To confirm the expression level, functional role, and impact on disulfidptosis of ABI3, the pivotal gene of the model, validation experiments were carried out .
The developed prognostic model successfully categorized LGG patients into two distinct risk groups: high and low. There was a noticeable difference in the time the groups survived, which was statistically significant. The model's predictive accuracy was substantiated through two independent external validation cohorts. Additional evaluations of the immune microenvironment and the potential for immunotherapy indicated that this risk classification could function as a practical roadmap for LGG treatment using immune-based therapies. Cellular experiments demonstrated that suppressing the crucial ABI3 gene in the predictive model significantly reduced the migratory and invasive abilities of both SHG44 and U251 cell lines while also triggering cytoskeletal retraction and increased cell pseudopodia.
The research suggests that the prognostic pattern relying on genes linked to disulfidptosis can provide valuable insights into the clinical outcomes, tumor characteristics, and immune alterations in patients with LGG. This could pave the way for early interventions and suggests that ABI3 might be a potential therapeutic target for disulfidptosis.
细胞程序性坏死是一种新定义的细胞死亡类型，在低级别胶质瘤（LGG）等恶性肿瘤的发展和进展中，它已成为一种重要的调控过程。然而，由于该领域的研究有限，LGG 中细胞程序性坏死的确切生物学机制仍有待揭示。
我们从 TCGA 和 CGGA 数据库中获取 LGG 数据，并进行了综合加权共表达网络分析、单样本基因集富集分析和转录组差异表达分析。我们使用 Cox 回归、LASSO 回归和 SVM-RFE 等机器学习方法发现了 9 个与细胞程序性坏死相关的基因，并构建了预测 LGG 患者的模型。为了验证模型中关键基因 ABI3 的表达水平、功能作用和对细胞程序性坏死的影响，我们进行了验证实验。
所开发的预后模型成功地将 LGG 患者分为高风险和低风险两个不同的风险组。两组的生存时间存在明显差异，且具有统计学意义。该模型通过两个独立的外部验证队列得到了验证。对免疫微环境和免疫治疗潜力的进一步评估表明，这种风险分类可以作为 LGG 免疫治疗的实用治疗方案。细胞实验表明，在预测模型中抑制关键基因 ABI3 可显著降低 SHG44 和 U251 细胞系的迁移和侵袭能力，同时触发细胞骨架收缩和增加细胞伪足。
该研究表明，基于与细胞程序性坏死相关基因的预后模式可为 LGG 患者的临床结局、肿瘤特征和免疫改变提供有价值的见解。这可能为早期干预提供依据，并提示 ABI3 可能是细胞程序性坏死的潜在治疗靶点。
