Liu Lu, Wang Bing, Ma Xiaoya, Tan Lei, Wei Xudong
The First Clinical Medical College of Lanzhou University, Lanzhou, China.
Department of E.N.T., Gansu Provincial Hospital, Lanzhou, China.
Front Pharmacol. 2025 Mar 20;16:1513948. doi: 10.3389/fphar.2025.1513948. eCollection 2025.
Laryngeal cancer (LC) is characterized by high mortality and remains challenging in prognostic evaluation and treatment benefits. Ubiquitin-related genes (UbRGs) are widely involved in cancer initiation and progression, but their potential value in LC is unknown.
RNA-seq and clinical data of LC were obtained from TCGA and GEO. UbRGs that independently influenced the overall survival (OS) of LC patients were screened with differential expression, COX and LASSO regression analyses. A prognostic signature was then established and assessed for its predictive value, stability and applicability using Kaplan-Meier analysis and receiver operating characteristic curves. The nomogram was further generated in combination with the signature and clinical characteristics. Characterization of immune properties and prediction of drug sensitivity were investigated on the signature-based subgroups using a panel of platforms. Verification of gene expression was conducted with Western blot, qRT-PCR and ELISA, ultimately.
PPARG, LCK and LHX1 were identified and employed to construct the UbRGs-based prognostic signature, showing a strong ability to discriminate LC patients with distinct OS in TCGA-LC and GSE65858, and excellent applicability in most clinical conditions. The nomogram showed higher predictive value and net clinical benefit than traditional indicators. As evaluated, the low-risk group had a more activated immune function, higher infiltration of anti-cancer immune cells and stronger expression of immune-promoting cytokines than the high-risk group. Immune properties were also correlated with individual signature genes. PPARG and LHX1 were negatively correlated, whereas LCK positively correlated, with the immuno-promoting microenvironment. Additionally, chemotherapy would be more effective in high-risk patients, while immune checkpoint inhibitors would be more effective in low-risk patients. Finally, dysregulation of the signature genes was confirmed in LC cell lines by Western blot, and PPARG knockdown significantly reduced the expression of the immunosuppressive cytokines IL6, TGFB1, TGFB2 and VEGFC by qRT-PCR and ELISA.
We have developed a UbRGs-based signature for LC prognostic evaluation that is valuable in clinical application, indicative of the immune microenvironment and beneficial for individualized treatment guidance.
喉癌（LC）具有高死亡率的特点，在预后评估和治疗获益方面仍然具有挑战性。泛素相关基因（UbRGs）广泛参与癌症的发生和发展，但其在喉癌中的潜在价值尚不清楚。
从TCGA和GEO获取喉癌的RNA测序和临床数据。通过差异表达、COX和LASSO回归分析筛选出独立影响喉癌患者总生存期（OS）的泛素相关基因。然后建立预后特征，并使用Kaplan-Meier分析和受试者工作特征曲线评估其预测价值、稳定性和适用性。结合该特征和临床特征进一步生成列线图。使用一组平台对基于特征的亚组进行免疫特性表征和药物敏感性预测。最终通过蛋白质免疫印迹、qRT-PCR和ELISA对基因表达进行验证。
鉴定出PPARG、LCK和LHX1，并用于构建基于泛素相关基因的预后特征，该特征在TCGA-LC和GSE65858中具有很强的区分不同总生存期喉癌患者的能力，并且在大多数临床情况下具有出色的适用性。列线图显示出比传统指标更高的预测价值和净临床获益。评估结果显示，低风险组比高风险组具有更活跃的免疫功能、更高的抗癌免疫细胞浸润和更强的免疫促进细胞因子表达。免疫特性也与个体特征基因相关。PPARG和LHX1与免疫促进微环境呈负相关，而LCK与免疫促进微环境呈正相关。此外，化疗在高风险患者中更有效，而免疫检查点抑制剂在低风险患者中更有效。最后，通过蛋白质免疫印迹在喉癌细胞系中证实了特征基因的失调，并且通过qRT-PCR和ELISA发现PPARG敲低显著降低了免疫抑制细胞因子IL6、TGFB1、TGFB2和VEGFC的表达。
我们开发了一种基于泛素相关基因特征用于喉癌预后评估，该特征在临床应用中具有价值，可指示免疫微环境，并有利于个体化治疗指导。
