Liu Yingjun, Li Xiao, Lian Kena, Wang Youcai, Huo Mingke, Li Zhi, Chen Xiaobin, Wang Jianwei
Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China.
The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Sci Rep. 2025 Sep 26;15(1):33308. doi: 10.1038/s41598-025-08881-8.
Gastric cancer ranks among the most prevalent forms of cancer worldwide. Recent rapid advancements in diagnostic methods, neoadjuvant or adjuvant therapies, and surgical procedures have significantly improved survival rates for patients with gastric cancer. Nonetheless, these benefits have not yet reached the majority of individuals affected. Previous research has indicated that USP2, a component of the ubiquitin system, plays a crucial role in reshaping the proteome and enhancing the prognosis of diseases. However, the current understanding of USP2 expression and the associated pathways in gastric cancer remains unclear. The differential expression of USP2 was examined in pan-cancer, with a particular focus on its expression in gastric cancer cells and patients. Additionally, the impact of USP2 on the proliferation, migration, and apoptosis of gastric cancer cells was explored via CCK8, transwell, and invasion assays. RNA sequencing was employed to investigate pathways associated with USP2, and RT-qPCR and western blotting were utilized to confirm the expression of related pathway genes and proteins. The prognostic value of a model derived from USP2 expression was assessed and validated. USP2 expression was significantly reduced in gastric cancer cells and patient samples (p < 0.05). Patients with low USP2 expression are primarily associated with genetic variations, neoantigen loads, microsatellite instability (MSI) scores, and immune cell infiltration (p < 0.05). The overexpression of USP2 suppresses proliferation, migration, and cell cycle progression while enhancing apoptosis in GC cells. Concurrently, we identified 865 genes whose expression was downregulated. KEGG and GSEA enrichment analyses revealed significant suppression of the focal adhesion and ECM receptor interaction pathways following USP2 overexpression. A genomic model derived from USP2 was constructed and validated for its reliability in predicting patient prognosis. The expression of USP2 was positively correlated with sensitivity to small-molecule drugs, including entinostat, SB590885, and PF-562,271. USP2 acts as a negative regulator of gastric cancer progression. Consequently, USP2 has the potential to be utilized as a therapeutic target to improve the clinical prognosis and survival rates of patients.
胃癌是全球最常见的癌症形式之一。近年来，诊断方法、新辅助或辅助治疗以及手术程序的迅速发展显著提高了胃癌患者的生存率。尽管如此，这些益处尚未惠及大多数受影响的个体。先前的研究表明，泛素系统的组成部分USP2在重塑蛋白质组和改善疾病预后方面发挥着关键作用。然而，目前对USP2在胃癌中的表达及相关途径的了解仍不清楚。研究了USP2在泛癌中的差异表达，特别关注其在胃癌细胞和患者中的表达。此外，通过CCK8、transwell和侵袭实验探讨了USP2对胃癌细胞增殖、迁移和凋亡的影响。采用RNA测序研究与USP2相关的途径，并利用RT-qPCR和蛋白质印迹法确认相关途径基因和蛋白质的表达。评估并验证了基于USP2表达的模型的预后价值。USP2在胃癌细胞和患者样本中的表达显著降低（p<0.05）。USP2低表达的患者主要与基因变异、新抗原负荷、微卫星不稳定性（MSI）评分和免疫细胞浸润有关（p<0.05）。USP2的过表达抑制了GC细胞的增殖、迁移和细胞周期进程，同时增强了细胞凋亡。同时，我们鉴定出865个表达下调的基因。KEGG和GSEA富集分析显示，USP2过表达后粘着斑和ECM受体相互作用途径受到显著抑制。构建了基于USP2的基因组模型，并验证了其在预测患者预后方面的可靠性。USP2的表达与对小分子药物（包括恩替诺司他、SB590885和PF-562,271）的敏感性呈正相关。USP2作为胃癌进展的负调节因子。因此，USP2有潜力被用作治疗靶点，以改善患者的临床预后和生存率。
