Zhuang Yuxiang, Li Xiaofeng
Department of Radiology, the Third Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Medicine (Baltimore). 2025 Jan 17;104(3):e40240. doi: 10.1097/MD.0000000000040240.
Osteosarcoma is a malignant bone tumor originating from mesenchymal tissue. Recent studies have found that the tumor inflammatory microenvironment plays an important role in promoting the malignant characteristics and metastatic potential of malignant tumors. Pyroptosis, an inflammatory programmed cell death, elicits immune responses that exhibit anti-tumor effects through released factors and contents. Therefore, improving anti-tumor immunity by targeting osteosarcoma-related pyroptosis genes and pathways may be of great significance in delaying early metastasis of osteosarcoma and improving patient survival rate. The study aimed to identify pyroptosis-related genes and biomarkers in osteosarcoma, predicting therapeutic drugs targeting these genes. Gene expression profiles of osteosarcoma were retrieved from Gene Expression Omnibus and cross-referenced with GeneCards and Comparative Toxicogenomics Database to identify differentially expressed pyroptosis-related genes. We conducted enrichment analysis on intersecting genes to identify their biological processes and signaling pathways and assessed immune cell composition in the tumor microenvironment through immune infiltration analysis. In addition, we further utilized Cytoscape software to screen out the top 10 genes with Degree values among the intersected genes as hub genes and performed GSEA analysis and drug prediction based on the hub genes. A total of 22 differentially expressed pyroptosis-related genes were identified in osteosarcoma, with 10 of them (TP53, CYCS, IL-1A, IL-1B, IL-18, CASP-3, CASP-8, IL-6, TNF, CASP-1) pinpointed as hub genes. Enrichment analysis found that the 22 intersection genes are mainly associated with pyroptosis, apoptosis, immune regulation, and related biological processes. The results of data validation targeting hub genes suggest that IL-18, CASP-1, and CASP-8 may be key genes involved in the regulation of pyroptosis in osteosarcoma. Immune infiltration analysis shows statistical differences in the distribution of immune cells like naive B cells, monocytes, M2 macrophages, and dendritic/mast cells, suggesting they play a role in the osteosarcoma tumor microenvironment. Hub gene drug targets suggest Triethyl phosphate, Plinabulin, and Siltuximab as potential osteosarcoma treatments. Our findings suggest potential mechanisms of action for 22 pyroptosis-related genes in osteosarcoma and preliminarily predicted that the occurrence of osteosarcoma is closely related to pyroptosis, apoptosis, and immune regulation. Predicted Triethyl phosphate, Plinabulin, Siltuximab as potential osteosarcoma treatments.
骨肉瘤是一种起源于间充质组织的恶性骨肿瘤。最近的研究发现，肿瘤炎症微环境在促进恶性肿瘤的恶性特征和转移潜能方面发挥着重要作用。细胞焦亡是一种炎症程序性细胞死亡，通过释放因子和内容物引发具有抗肿瘤作用的免疫反应。因此，通过靶向骨肉瘤相关的细胞焦亡基因和通路来提高抗肿瘤免疫力，对于延缓骨肉瘤的早期转移和提高患者生存率可能具有重要意义。本研究旨在识别骨肉瘤中与细胞焦亡相关的基因和生物标志物，预测靶向这些基因的治疗药物。从基因表达综合数据库（Gene Expression Omnibus）中检索骨肉瘤的基因表达谱，并与基因卡片（GeneCards）和比较毒理基因组学数据库（Comparative Toxicogenomics Database）进行交叉引用，以识别差异表达的细胞焦亡相关基因。我们对交集基因进行富集分析，以确定它们的生物学过程和信号通路，并通过免疫浸润分析评估肿瘤微环境中的免疫细胞组成。此外，我们进一步利用Cytoscape软件从交集中筛选出度值最高的前10个基因作为枢纽基因，并基于枢纽基因进行基因集富集分析（GSEA）和药物预测。在骨肉瘤中总共鉴定出22个差异表达的细胞焦亡相关基因，其中10个（TP53、CYCS、IL-1A、IL-1B、IL-18、CASP-3、CASP-8、IL-6、TNF、CASP-1）被确定为枢纽基因。富集分析发现，这22个交集基因主要与细胞焦亡、凋亡、免疫调节及相关生物学过程有关。针对枢纽基因的数据验证结果表明，IL-18、CASP-1和CASP-8可能是参与骨肉瘤细胞焦亡调控的关键基因。免疫浸润分析显示，幼稚B细胞、单核细胞、M2巨噬细胞和树突状/肥大细胞等免疫细胞的分布存在统计学差异，表明它们在骨肉瘤肿瘤微环境中发挥作用。枢纽基因药物靶点表明磷酸三乙酯、普利纳布林和西妥昔单抗是骨肉瘤的潜在治疗药物。我们的研究结果揭示了22个细胞焦亡相关基因在骨肉瘤中的潜在作用机制，并初步预测骨肉瘤的发生与细胞焦亡、凋亡和免疫调节密切相关。预测磷酸三乙酯、普利纳布林、西妥昔单抗为骨肉瘤的潜在治疗药物。
