Department of Gastroenterology, Baiyun Branch, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Department of Gastrointestinal Surgery, Shunde Hospital, Southern Medical University, Foshan, China.
Front Immunol. 2024 Sep 27;15:1409149. doi: 10.3389/fimmu.2024.1409149. eCollection 2024.
Recent research has found a new way of cell death: disulfidptosis. Under glucose starvation, abnormal accumulation of disulfide molecules such as Cystine in Solute Carrier Family 7 Member 11 (SLC7A11) overexpression cells induced disulfide stress to trigger cell death. The research on disulfidptosis is still in its early stages, and its role in the occurrence and development of colorectal malignancies is still unclear.
In this study, we employed bioinformatics methods to analyze the expression and mutation characteristics of disulfidptosis-related genes (DRGs) in colorectal cancer. Consensus clustering analysis was used to identify molecular subtypes of Colorectal Adenocarcinoma (COAD) associated with disulfidptosis. The biological behaviors between subtypes were analyzed to explore the impact of disulfidptosis on the tumor microenvironment. Constructing and validating a prognostic risk model for COAD using diverse data. The influence of key genes on prognosis was evaluated through SHapley Additive exPlanations (SHAP) analysis, and the predictive capability of the model was assessed using Overall Survival analysis, Area Under Curve and risk curves. The immunological status of different patients and the prediction of drug treatment response were determined through immune cell infiltration, TMB, MSI status, and drug sensitivity analysis. Single-cell analysis was employed to explore the expression of genes at the cellular level, and finally validated the expression of key genes in clinical samples.
By integrating the public data from two platforms, we identified 2 colorectal cancer subtypes related to DRGs. Ultimately, we established a prognosis risk model for COAD using 7 genes (FABA4+GIPC2+EGR3+HOXC6+CCL11+CXCL10+ITLN1). SHAP analysis can further explained the positive or negative impact of gene expression on prognosis. By dividing patients into high-risk and low-risk groups, we found that patients in the high-risk group had poorer prognosis, higher TMB, and a higher proportion of MSI-H and MSI-L statuses. We also predicted that drugs such as 5-Fluorouracil, Oxaliplatin, Gefitinib, and Sorafenib would be more effective in low-risk patients, while drugs like Luminesib and Staurosporine would be more effective in high-risk patients. Single-cell analysis revealed that these 7 genes not only differ at the level of immune cells but also in epithelial cells, fibroblasts, and myofibroblasts, among other cell types. Finally, the expression of these key genes was verified in clinical samples, with consistent results.
Our research findings provide evidence for the role of disulfidptosis in COAD and offer new insights for personalized and precise treatment of COAD.
最近的研究发现了一种新的细胞死亡方式：二硫键细胞凋亡。在葡萄糖饥饿下，溶质载体家族 7 成员 11（SLC7A11）过表达细胞中异常积累胱氨酸等二硫键分子会引发二硫键应激，从而触发细胞死亡。二硫键细胞凋亡的研究仍处于早期阶段，其在结直肠恶性肿瘤的发生和发展中的作用尚不清楚。
本研究采用生物信息学方法分析了结直肠癌中二硫键细胞凋亡相关基因（DRGs）的表达和突变特征。采用共识聚类分析鉴定与二硫键细胞凋亡相关的结直肠腺癌（COAD）分子亚型。分析不同亚型之间的生物学行为，以探讨二硫键细胞凋亡对肿瘤微环境的影响。使用多种数据构建和验证 COAD 的预后风险模型。通过 SHapley Additive exPlanations（SHAP）分析评估关键基因对预后的影响，通过总体生存分析、曲线下面积和风险曲线评估模型的预测能力。通过免疫细胞浸润、TMB、MSI 状态和药物敏感性分析确定不同患者的免疫状态和药物治疗反应的预测。通过单细胞分析探讨基因在细胞水平上的表达，并最终在临床样本中验证关键基因的表达。
通过整合来自两个平台的公共数据，我们确定了与 DRGs 相关的 2 种结直肠癌细胞亚型。最终，我们使用 7 个基因（FABA4+GIPC2+EGR3+HOXC6+CCL11+CXCL10+ITLN1）建立了结直肠癌的预后风险模型。SHAP 分析可以进一步解释基因表达对预后的积极或消极影响。通过将患者分为高风险和低风险组，我们发现高风险组患者的预后较差，TMB 较高，且 MSI-H 和 MSI-L 状态的比例较高。我们还预测，在低风险患者中，药物如 5-氟尿嘧啶、奥沙利铂、吉非替尼和索拉非尼可能更有效，而在高风险患者中，药物如 Luminesib 和 Staurosporine 可能更有效。单细胞分析表明，这些 7 个基因不仅在免疫细胞水平上存在差异，而且在上皮细胞、成纤维细胞和肌成纤维细胞等其他细胞类型中也存在差异。最后，在临床样本中验证了这些关键基因的表达，结果一致。
我们的研究结果为二硫键细胞凋亡在 COAD 中的作用提供了证据，并为 COAD 的个性化和精准治疗提供了新的思路。
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