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TGM2 受转录因子 NR3C1 调控，驱动 p38 MAPK 介导的肺鳞状细胞癌肿瘤进展和免疫逃逸

英文原题：TGM2 regulated by transcription factor NR3C1 drives p38 MAPK-mediated tumor progression and immune evasion in lung squamous cell carcinoma.

查看英文原题

TGM2 regulated by transcription factor NR3C1 drives p38 MAPK-mediated tumor progression and immune evasion in lung squamous cell carcinoma.

PubMed 2025/09/18（内容时间） Front Immunol Q1 · IF 7（JCR 2025）

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技术：NK 细胞地区：中国
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研究概要

TGM2 通过 p38 MAPK 激活驱动 LUSC 进展并塑造免疫抑制微环境，其转录受 NR3C1 调控。本研究支持 TGM2 作为预后生物标志物，并提示其作为治疗靶点的潜力，这可能为未来的联合免疫治疗策略提供依据。

研究思路结论见上方概要

背景

肺鳞状细胞癌（LUSC）恶性程度高，治疗靶点有限。既往研究表明，转谷氨酰胺酶2（TGM2）调控肿瘤微环境，但其驱动LUSC进展和免疫逃逸的机制尚不清楚。

方法

采用TCGA LUSC队列分析TGM2的预后价值。通过随机森林算法筛选关键基因。在NCI-H520和SK-MES-1细胞系中进行功能验证。蛋白质组学、GSEA和TIMER2.0评估下游通路和免疫浸润。转录调控数据库预测TGM2的上游转录因子，随后通过染色质免疫沉淀（ChIP）-qPCR进行验证。

结果

TGM2是LUSC的独立预后因素。TGM2高表达与总生存期（OS，P = 0.00018）和无病生存期（DFS，P = 0.00019）缩短相关。TGM2通过激活p38 MAPK信号通路促进LUSC细胞增殖、迁移、侵袭、克隆形成，并抑制凋亡。TGM2水平升高与免疫抑制性微环境相关：Th1（R = -0.186，P < 0.0001）和NK细胞浸润减少（R = -0.116，P = 0.0092），M2巨噬细胞（R = 0.164-0.528，P < 0.0001）和癌相关成纤维细胞浸润增加（R = 0.469，P < 0.0001）。NR3C1被鉴定为调控TGM2的关键转录因子。ChIP-qPCR分析证实NR3C1结合于TGM2启动子内的特定位点（921-935），且二者表达呈强正相关（R = 0.53，P < 0.0001）。

展开英文摘要原文
BACKGROUND

Lung squamous cell carcinoma (LUSC) is highly malignant with limited therapeutic targets. Prior studies indicate transglutaminase 2 (TGM2) regulates the tumor microenvironment, but its mechanisms in driving LUSC progression and immune evasion remain unclear.

METHODS

The prognostic value of TGM2 was analyzed using the TCGA LUSC cohort. Key genes were screened via random forest algorithm. Functional validation was performed in NCI-H520 and SK-MES-1 cell lines. Proteomics, GSEA, and TIMER2.0 assessed downstream pathways and immune infiltration. Transcriptional regulatory databases predicted the upstream transcription factors of TGM2, which was then validated by chromatin immunoprecipitation (ChIP)-qPCR.

RESULTS

TGM2 was an independent prognostic factor for LUSC. High TGM2 expression correlated with reduced overall survival (OS, P = 0.00018) and disease-free survival (DFS, P = 0.00019). TGM2 promoted proliferation, migration, invasion, clonogenicity, and suppressed apoptosis in LUSC cells by activating p38 MAPK signaling. Elevated TGM2 levels were associated with an immunosuppressive microenvironment: decreased Th1 (R = -0.186, P < 0.0001) and NK cell infiltration (R = -0.116, P = 0.0092), and increased M2 macrophage (R = 0.164-0.528, P < 0.0001) and cancer-associated fibroblast infiltration (R = 0.469, P < 0.0001). NR3C1 was identified as a key transcription factor regulating TGM2. ChIP-qPCR analysis confirmed that NR3C1 binds to a specific site (921-935) within the TGM2 promoter, and their expression showed a strong positive correlation (R = 0.53, P < 0.0001).

CONCLUSION

TGM2 drives LUSC progression via p38 MAPK activation and shapes an immunosuppressive microenvironment, which is transcriptionally regulated by NR3C1. This study supports TGM2 as a prognostic biomarker and suggests its potential as a therapeutic target, which may inform future combination immunotherapy strategies.

论文信息

作者
Lin C、Li S、Yi L、Zhou H、Xiao Z、Yang Z、Chen Q、Peng X
单位
Department of Respiratory and Critical Care Medicine, Yueyang People's Hospital of Hunan Normal University, Yueyang,&#xa0;China.China
期刊
Frontiers in immunology2025
原文标识
PubMed 41050683　·　DOI 10.3389/fimmu.2025.1595907

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