Shi Yuan-Xiang, Wang Jia, Jiang Zhen-Lin, Yan Jian-Hua
Institute of Clinical Medicine, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, China.
Department of Cardiac Thoracic Surgery, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, China.
J Cancer. 2025 Jan 20;16(4):1363-1378. doi: 10.7150/jca.104837. eCollection 2025.
Ubiquitination is involved in several tumor immunomodulatory processes, and targeting E3 ubiquitin ligases has substantial potential in cancer therapy. In this study, the key E3 ubiquitin ligases involved in regulating the malignant progression of LUAD were studied. We first systematically investigated the expression landscape, prognosis, immune infiltration, drug sensitivity, and potential molecular mechanisms of these hub genes in LUAD. was localized by immunofluorescence analysis in tumor cell lines, and its expression level was determined by immunohistochemistry on tissue chips. Single-cell analysis and spatial transcriptomics were used to determine expression in multiple cell types. Molecular docking was performed via computer simulation to verify the ability of drugs to bind to target genes. We found that these hub genes are specifically overexpressed in LUAD and are associated with poor patient prognosis. All five E3 ubiquitin ligase genes were negatively correlated with B cells and dendritic cells but positively related to neutrophil immune infiltration. In addition, analysis of the CTRP and GDSC databases revealed that the sensitivity to multiple antitumor drugs increased when was highly expressed. GSEA enrichment analysis demonstrated that the G2M_CHECKPOINT, MTORC1_SIGNALING, OXIDATIVE_PHOSPHORYLATION, and GLYCOLYSIS signaling pathways were enriched when was highly expressed. Further correlation analysis indicated that was positively correlated with the expression of the key genes mTOR, S6K1, and 4E-BP1 and the autophagy-related gene ULK1 in the mTORC1 signaling pathway. These key E3 ubiquitin ligases serve as potential molecular biomarkers for predicting the prognosis, immune response, and drug sensitivity of LUAD patients.
泛素化参与多种肿瘤免疫调节过程，靶向E3泛素连接酶在癌症治疗中具有巨大潜力。在本研究中，我们对参与调控肺腺癌恶性进展的关键E3泛素连接酶进行了研究。我们首先系统地研究了这些核心基因在肺腺癌中的表达谱、预后、免疫浸润、药物敏感性及潜在分子机制。通过免疫荧光分析在肿瘤细胞系中定位其表达，并通过组织芯片上的免疫组化确定其表达水平。利用单细胞分析和空间转录组学确定其在多种细胞类型中的表达。通过计算机模拟进行分子对接，以验证药物与靶基因的结合能力。我们发现这些核心基因在肺腺癌中特异性高表达，且与患者预后不良相关。所有五个E3泛素连接酶基因均与B细胞和树突状细胞呈负相关，但与中性粒细胞免疫浸润呈正相关。此外，对CTRP和GDSC数据库的分析显示，当该基因高表达时，对多种抗肿瘤药物的敏感性增加。基因集富集分析表明，当该基因高表达时，G2M_CHECKPOINT、MTORC1_SIGNALING、OXIDATIVE_PHOSPHORYLATION和GLYCOLYSIS信号通路富集。进一步的相关性分析表明，该基因与mTORC1信号通路中的关键基因mTOR、S6K1和4E-BP1以及自噬相关基因ULK1的表达呈正相关。这些关键的E3泛素连接酶可作为预测肺腺癌患者预后、免疫反应和药物敏感性的潜在分子生物标志物。
