以SERPINE1为中心的炎症特征与喉鳞状细胞癌的治疗耐药和生存相关。

文献信息

中文摘要

背景： 尽管治疗取得了进展，喉鳞状细胞癌（LSCC）的预后仍然很差。更准确的预后评估模型有助于指导个体化治疗并改善预后。慢性炎症促进肿瘤发生，但炎症反应相关基因（IRGs）在LSCC预后中的作用尚未得到充分探索。本研究旨在构建LSCC的IRG预后特征，并进一步剖析核心IRG介导的免疫逃逸和化疗耐药机制。
方法： 从癌症基因组图谱（TCGA）中检索LSCC患者的转录谱和临床数据。IRGs来源于基因集富集分析（GSEA）标志基因集。我们鉴定了与LSCC生存结局相关的差异表达IRGs。随后使用最小绝对收缩和选择算子（LASSO）Cox回归分析选择关键IRGs，以建立炎症风险评分模型。该模型在TCGA队列中进行了内部验证，并使用独立的基因表达综合（GEO）数据集进行了外部验证。我们进一步评估了该模型与肿瘤免疫微环境的关联以及IRGs对化疗反应的影响。最后，在LSCC细胞系中对感兴趣的标志IRG的功能作用进行了实验验证。
结果： 鉴定出四个显著的IRGs（AQP9、ITGA5、LCK、SERPINE1）用于构建风险评分模型。该模型将LSCC患者分为不同的预后组：TCGA队列：5年曲线下面积（AUC）=0.836，P<0.001；GSE25727队列：5年AUC=0.706，P=0.02；GSE27020队列：5年AUC=0.798，P<0.01。多变量分析证实风险评分是一个独立的预后因素（P<0.05）。高风险患者显示免疫细胞浸润（CD8+ T细胞、树突状细胞）减少和免疫通路受抑制。多算法免疫分析进一步揭示高风险LSCC中抗原呈递缺陷和抗肿瘤免疫浸润减少，促进肿瘤免疫逃逸。GSEA/基因本体论（GO）富集结合药物敏感性预测进一步揭示高风险肿瘤激活侵袭性信号传导并获得广泛的化疗耐药以及抗肿瘤免疫受损。SERPINE1可能与化疗耐药相关，并在LSCC组织中表现出最高的改变频率（主要是扩增）和过表达。其敲低显著抑制了LSCC细胞的增殖、迁移、侵袭和化疗耐药。免疫组织化学（IHC）证实肿瘤SERPINE1过表达（P=0.002 vs. 正常组织），与不良生存相关（P<0.001）。
结论： 4-IRG风险特征是一个可靠的预后指标，反映了LSCC中的免疫功能障碍。SERPINE1被验证为治疗靶点和生物标志物，丰富了我们对LSCC基因调控动态的理解。

英文摘要

BACKGROUND: Laryngeal squamous cell carcinoma (LSCC) prognosis remains poor despite treatment advances. More accurate prognostic assessment models can help guide individualized treatment and improve prognosis. Chronic inflammation contributes to tumorigenesis, yet inflammatory response-related genes (IRGs) in LSCC prognosis are underexplored. This study aimed to construct an IRG prognostic signature for LSCC and further dissect core IRG-mediated mechanisms of immune escape and chemoresistance.
METHODS: Transcriptional profiles and clinical data from LSCC patients were retrieved from The Cancer Genome Atlas (TCGA). IRGs were sourced from Gene Set Enrichment Analysis (GSEA) hallmark gene set. We identified differentially expressed IRGs linked to survival outcomes in LSCC. Key IRGs were subsequently selected using least absolute shrinkage and selection operator (LASSO) Cox regression analysis to establish an inflammatory risk score model. This model underwent internal validation within the TCGA cohort and external validation using independent Gene Expression Omnibus (GEO) datasets. We further assessed the model's association with the tumor immune microenvironment and the impact of IRGs on chemotherapy response. Finally, the functional roles of interested signature IRG were experimentally validated in LSCC cell lines.
RESULTS: Four significant IRGs (AQP9, ITGA5, LCK, SERPINE1) were identified to build the risk score model. The model stratified LSCC patients into distinct prognostic groups: TCGA cohort: 5-year area under the curve (AUC) =0.836, P<0.001; GSE25727 cohort: 5-year AUC =0.706, P=0.02; GSE27020 cohort: 5-year AUC =0.798, P<0.01. Multivariate analysis confirmed the risk score as an independent prognostic factor (P<0.05). High-risk patients showed reduced immune cell infiltration (CD8+ T cells, dendritic cells) and suppressed immune pathways. Multi-algorithm immune analysis further revealed defective antigen presentation and reduced anti-tumor immune infiltration in high-risk LSCC, promoting tumor immune escape. GSEA/Gene Ontology (GO) enrichment combined with drug sensitivity prediction further revealed that high-risk tumors activate invasive signaling and acquire broad chemoresistance alongside impaired anti-tumor immunity. SERPINE1 might be associated with chemotherapy resistance and exhibited the highest alteration frequency (predominantly amplification) and overexpression in LSCC tissues. Its knockdown significantly suppressed proliferation, migration, invasion and chemoresistance in LSCC cells. Immunohistochemistry (IHC) confirmed tumor SERPINE1 overexpression (P=0.002 vs. normal tissues), correlating with poor survival (P<0.001).
CONCLUSIONS: The 4-IRG risk signature is a reliable prognostic indicator reflecting immune dysfunction in LSCC. SERPINE1 is validated as a therapeutic target and biomarker, enriching our understanding of gene regulation dynamics in LSCC.