Jiang Zhihang, Li Xiaoqing, Hu Long, Jiang Zheng
Department of Gastroenterology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Front Immunol. 2025 May 20;16:1571446. doi: 10.3389/fimmu.2025.1571446. eCollection 2025.
Succinylation, a key post-translational modification, plays a crucial role in metabolic regulation and tumor progression. However, its influence on the tumor immune microenvironment and its prognostic implications remain unclear. A systematic pan-cancer analysis of succinylation-related molecular activities is needed.
Bulk transcriptomic, single-cell RNA sequencing, and spatial transcriptomic data across pan-cancer from TCGA, GEO, TISCH, and multiple other databases were analyzed. Succinylation scores were calculated using Gene Set Variation Analysis (GSVA). The interactions between succinylation scores, immune infiltration, tumor microenvironment, tumor mutational burden, and immunotherapy response were assessed. A succinylation-based prognostic model was constructed and validated in colorectal cancer (CRC) cohorts. PCED1A protein expression was evaluated by immunohistochemistry and Western blotting. The function of PCED1A in CRC was investigated through experiments.
Succinylation scores were significantly altered in multiple tumor types. Higher succinylation scores correlated with mitochondrial oxidative phosphorylation, while lower succinylation scores were linked to immune cell differentiation. Spatial transcriptomic analysis showed a negative correlation between succinylation scores and immune cell activity in tumor-adjacent regions. A prognostic model consisting of 11 succinylation-related genes (ATP6V1C2, CAPS, DAPK1, P4HA1, PCED1A, RASL10B, AGT, EREG, HYAL1, SARAF, and SLC4A4) was developed. High-risk patients exhibited significantly shorter overall survival. PCED1A was upregulated in CRC and positively associated with SIRT5. Overexpression of PCED1A promoted intracellular protein desuccinylation, along with enhanced CRC cell proliferation, migration, and invasion.
Our analysis demonstrates that succinylation-related molecular activities display distinct expression patterns across cancers, which are associated with metabolic regulation, immune modulation, and disease prognosis. The succinylation-based prognostic model provides a novel risk stratification tool for CRC, while PCED1A-dependent succinylation regulation may serve as a potential therapeutic target.
琥珀酰化是一种关键的翻译后修饰，在代谢调节和肿瘤进展中起关键作用。然而，其对肿瘤免疫微环境的影响及其预后意义仍不清楚。需要对琥珀酰化相关分子活性进行系统的泛癌分析。
分析了来自TCGA、GEO、TISCH和多个其他数据库的泛癌批量转录组学、单细胞RNA测序和空间转录组学数据。使用基因集变异分析（GSVA）计算琥珀酰化评分。评估了琥珀酰化评分、免疫浸润、肿瘤微环境、肿瘤突变负荷和免疫治疗反应之间的相互作用。构建了基于琥珀酰化的预后模型，并在结直肠癌（CRC）队列中进行了验证。通过免疫组织化学和蛋白质印迹法评估PCED1A蛋白表达。通过实验研究了PCED1A在CRC中的功能。
琥珀酰化评分在多种肿瘤类型中显著改变。较高的琥珀酰化评分与线粒体氧化磷酸化相关，而较低的琥珀酰化评分与免疫细胞分化相关。空间转录组学分析显示肿瘤邻近区域的琥珀酰化评分与免疫细胞活性呈负相关。开发了一个由11个琥珀酰化相关基因（ATP6V1C2、CAPS、DAPK1、P4HA1、PCED1A、RASL10B、AGT、EREG、HYAL1、SARAF和SLC4A4）组成的预后模型。高危患者的总生存期明显较短。PCED1A在CRC中上调，并与SIRT5呈正相关。PCED1A的过表达促进细胞内蛋白质去琥珀酰化，同时增强CRC细胞的增殖、迁移和侵袭。
我们的分析表明，琥珀酰化相关分子活性在不同癌症中表现出不同的表达模式，这与代谢调节、免疫调节和疾病预后相关。基于琥珀酰化的预后模型为CRC提供了一种新的风险分层工具，而PCED1A依赖性琥珀酰化调节可能成为潜在的治疗靶点。
