Lin Yi-Wei, Li Hui-Er, Hong Chao-Qun, Chen Zi-Ang, Liu Shu-Ping, Xu Yi-Wei, Wu Fang-Cai, Peng Yu-Hui
Department of Clinical Laboratory Medicine, Esophageal Cancer Prevention and Control Research Center, Chaoshan Branch of State Key Laboratory for Esophageal Cancer Prevention and Treatment, Cancer Hospital of Shantou University Medical College, Shantou, China.
Guangdong Esophageal Cancer Institute, Guangzhou, China.
Front Immunol. 2025 Aug 21;16:1632090. doi: 10.3389/fimmu.2025.1632090. eCollection 2025.
As a highly invasive gastrointestinal malignancy, esophageal squamous cell carcinoma (ESCC) carries with its high morbidity and mortality. Accumulating evidence indicates that abnormal activation of ubiquitination and deubiquitylation has been implicated in pathophysiology of ESCC. However, rare prognostic models for ubiquitination-related genes (URGs) and deubiquitylation-related genes (DRGs) have been built up in ESCC.
From training dataset GSE53624, the differentially expressed prognostic URGs and DRGs were identified to develop a prognostic signature, which was validated in GSE53622 and TCGA-ESCC dataset to show the robustness of the signature. To further confirm their prognosis value, the unsupervised clustering analysis was used to develop the molecular subtypes based on the prognostic URGs and DRGs. Differences in terms of biological function, immune status, and drug sensitivity were evaluated between high- and low-risk groups. The nomogram was constructed by combining the URGs and DRGs prognostic signature and clinical characteristics to improve prediction efficacy. Loss-of-function studies were conducted to explore the biological function of NEURL3 in ESCC.
The URGs and DRGs prognostic signature consisted of 11 genes and exhibited high accuracy in predicting prognosis of ESCC patient. Based on these 11 URGs and DRGs, two molecular subtypes of ESCC (C1 and C2) were identified, of which C2 subtype had significantly shorter overall survival time than that of C1 subtype. The function enrichment analysis showed that these genes play key roles in essential processes such as tumor metastasis and immune response. Moreover, the risk score was closely related to infiltration abundance of some types of immune cells, gene markers of immune cells and immune checkpoint-related markers. The drug sensitivity analysis showed that dacomitinib and talazoparib may serve as anti-ESCC drugs through targeting MAPK14. The nomogram was established by combining the URGs and DRGs signature with age and TNM stage, and it also showed enhanced prognostic predictive accuracy. The experiments showed that knockdown of NEURL3 inhibited the proliferation and motility of ESCC cells.
Based on the URGs and DRGs prognostic signature, a novel nomogram was constructed that could serve as a potentially reliable prognostic model and provide theoretical basis for uncovering potential therapeutic target in the treatment of ESCC.
食管鳞状细胞癌（ESCC）作为一种具有高度侵袭性的胃肠道恶性肿瘤，其发病率和死亡率都很高。越来越多的证据表明，泛素化和去泛素化的异常激活与ESCC的病理生理学有关。然而，在ESCC中，针对泛素化相关基因（URGs）和去泛素化相关基因（DRGs）的预后模型却很少建立。
从训练数据集GSE53624中，鉴定出差异表达的预后URGs和DRGs，以构建一个预后特征，该特征在GSE53622和TCGA-ESCC数据集中进行验证，以显示该特征的稳健性。为了进一步确认它们的预后价值，使用无监督聚类分析基于预后URGs和DRGs开发分子亚型。评估高风险组和低风险组在生物学功能、免疫状态和药物敏感性方面的差异。通过结合URGs和DRGs预后特征与临床特征构建列线图，以提高预测效能。进行功能丧失研究以探索NEURL3在ESCC中的生物学功能。
URGs和DRGs预后特征由11个基因组成，在预测ESCC患者预后方面表现出高准确性。基于这11个URGs和DRGs，鉴定出ESCC的两种分子亚型（C1和C2），其中C2亚型的总生存时间明显短于C1亚型。功能富集分析表明，这些基因在肿瘤转移和免疫反应等关键过程中发挥关键作用。此外，风险评分与某些类型免疫细胞的浸润丰度、免疫细胞的基因标志物和免疫检查点相关标志物密切相关。药物敏感性分析表明，达可替尼和他拉唑帕尼可能通过靶向MAPK14作为抗ESCC药物。通过将URGs和DRGs特征与年龄和TNM分期相结合建立列线图，其也显示出增强的预后预测准确性。实验表明，敲低NEURL3可抑制ESCC细胞的增殖和运动。
基于URGs和DRGs预后特征，构建了一种新型列线图，其可作为一种潜在可靠的预后模型，并为揭示ESCC治疗中的潜在治疗靶点提供理论依据。
