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中华肺部疾病杂志(电子版) ›› 2026, Vol. 19 ›› Issue (01) : 28 -35. doi: 10.3877/cma.j.issn.1674-6902.2026.01.005

论著

TFF家族通过ECM受体互作通路驱动肺腺癌进展:多组学预后模型与杯状细胞机制研究
代静1, 袁婷1, 张硕辛2, 毛杨3, 范会业3,()   
  1. 1400037 重庆,陆军(第三)军医大学第二附属医院心内科
    2400037 重庆,陆军(第三)军医大学第二附属医院呼吸内科
    3400037 重庆,陆军(第三)军医大学第二附属医院临床医学研究中心
  • 收稿日期:2025-08-20 出版日期:2026-02-25
  • 通信作者: 范会业
  • 基金资助:
    国家自然科学基金面上项目(82270821)

TFF drives lung adenocarcinoma progression via the ECM receptor interaction pathway: A multi-omics prognostic model and goblet cell mechanism analysis

Jing Dai1, Ting Yuan1, Shuoxin Zhang2, Yang Mao3, Huiye Fan3,()   

  1. 1Department of Cardiology, Second Affiliated Hospital, Army Medical University, Chongqing 400037, China
    2Department of respiratory, Second Affiliated Hospital, Army Medical University, Chongqing 400037, China
    3Clinical Medical Research Center, Second Affiliated Hospital, Army Medical University, Chongqing 400037, China
  • Received:2025-08-20 Published:2026-02-25
  • Corresponding author: Huiye Fan
引用本文:

代静, 袁婷, 张硕辛, 毛杨, 范会业. TFF家族通过ECM受体互作通路驱动肺腺癌进展:多组学预后模型与杯状细胞机制研究[J/OL]. 中华肺部疾病杂志(电子版), 2026, 19(01): 28-35.

Jing Dai, Ting Yuan, Shuoxin Zhang, Yang Mao, Huiye Fan. TFF drives lung adenocarcinoma progression via the ECM receptor interaction pathway: A multi-omics prognostic model and goblet cell mechanism analysis[J/OL]. Chinese Journal of Lung Diseases(Electronic Edition), 2026, 19(01): 28-35.

目的

构建基于多组学特征的预后风险模型,系统解析杯状细胞相关黏附分子(cup-related adhesion molecule)在肺腺癌中的预后意义,为精准诊疗提供生物标志物参考。

方法

通过整合TCGA-LUAD(n=598)、GTEx正常肺组织(n=110)及3个GEO(gene expression omnibus,基因表达综合数据库)队列(n=189)进行差异表达分析,采用LASSO-Cox回归构建预后模型,并通过NCI-H1975细胞系的实时定量聚合酶链式反应(quantitative polymerase chain reaction, RT-qPCR)、蛋白质印迹法(western blot, WB)实验验证靶基因表达。

结果

LUAD样本中共筛选出1583个差异表达基因(|log2FC|>1, FDR<0.05),包括883个上调基因和700个下调基因。GO/KEGG分析显示差异基因显著富集于细胞周期调控和细胞外基质(extracellular matrix, ECM)-受体相互作用通路。多因素Cox回归证实三叶因子1(trefoil factorl, TFF1)为独立预后因素(HR=1.22, 95%CI:0.082~0.109, P<0.001),其参与构建的5基因模型在测试集的C-index达0.71。单细胞转录组分析(n=17)显示,TFF家族基因在肿瘤微环境杯状细胞中特异性高表达(log2FC>2, P<0.001),与临床分期呈正相关(Spearman ρ=0.68,P=1.3×107)。RT-qPCR和WB实验结果表明,LUAD细胞系的5个细胞黏附关键生物标志物(TFF1、TFF2、TFF3、REG4和SPINK4)表达差异显著(P<0.05)。

结论

通过多组学数据分析构建的5基因预后模型(TFF1/2/3、REG4、SPINK4)在独立队列中验证有效(AUC=0.77),其中TFF1通过杯状细胞驱动肿瘤进展,为肺腺癌的液体活检和靶向治疗提供了新型组合标志物。

Objective

To construct a prognostic risk model based on multi-omics features and systematically analyze the prognostic value of goblet cell-related adhesion molecules in lung adenocarcinoma (LUAD), providing biomarker references for precision diagnosis and treatment.

Methods

This study integrated TCGA-LUAD (n=598), GTEx normal lung tissue (n=110), and three GEO cohorts (GSE31210, etc., n=189) for differential expression analysis. A prognostic model was constructed using LASSO-Cox regression, and the expression of target genes was validated through real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot (WB) experiments in the NCI-H1975 cell line.

Results

1 583 differentially expressed genes (|log2FC|>1, FDR<0.05) were identified in LUAD samples, including 883 upregulated and 700 downregulated genes. GO/KEGG analysis revealed that these genes were significantly enriched in cell cycle regulation (GO: 0045786, P=1.4e-07) and the extracellular matrix-receptor(ECM) interaction pathway (hsa 04512, P=1.8e-09). Additionally, multivariate Cox regression confirmed TFF1 as an independent prognostic factor (HR=1.22, 95%CI: 0.082~0.109, P<0.001). The 5-gene model constructed with TFF1 achieved a C-index of 0.71 in the test set. Single-cell transcriptome analysis (n=17) showed that TFF family genes were specifically highly expressed in goblet cells within the tumor microenvironment (log2FC>2, P<0.001) and positively correlated with clinical stage (Spearman ρ=0.68, P=1.3×107). RT-qPCR and WB experiments demonstrated significant differences in the expression of five key adhesion biomarkers (TFF1, TFF2, TFF3, REG4, and SPINK4) in LUAD cell lines (P<0.05).

Conclusion

The 5-gene prognostic model (TFF1/2/3, REG4, SPINK4) constructed through multi-omics data analysis was validated in an independent cohort (AUC=0.77). TFF1 drives tumor progression via goblet cells, offering a novel combination biomarker for liquid biopsy and targeted therapy in LUAD.

表1 LUAD转录组数据来源
表2 目的基因的引物名称、序列
图1 肺腺癌中差异表达显著的基因。图A为来自TCGA-LUAD、GSE115002和GSE116859数据集的差异基因表达;图B为核心基因的拓扑结构图;图C为核心基因的差异表达火山图;图D为DEGs的GO分析。BP为生物过程;CC为细胞组成;MF为分子功能;图E为DEGs的KEGG分析
图2 生存模型的构建和分析。图A为OS的LASSO-Cox回归模型;图B为OS的LASSO回归模型的调整参数;图C为根据OS的风险因子图示;图D为高风险和低风险亚组之间OS患者的Kaplan-Meier曲线;图E为PFS的LASSO-Cox回归模型;图F为PFS的LASSO回归模型的调整参数;图G为根据PFS的风险因子图示;图H为高风险和低风险亚组之间PFS患者的Kaplan-Meier曲线
表3 LASSO回归模型中的5基因预后特征参数
图3 随机森林图的构建。图A为风险森林图;图B为模型的1年、3年和5年的ROC曲线;图C为基于模型预测和观察到的1年、3年和5年存活率之间的校准曲线
图4 LUAD的单细胞转录组特征及杯状细胞动态演化。图A为单细胞转录组分群;图B为不同分组每细胞比例;图C为核心基因在每细胞上的表达;图D为杯状细胞拟时间轨迹构建;图E为基因表达动态;图F为核心基因表达水平沿分化轨迹显著上升
图5 关键生物标志物的表达的验证。图A为在NCI-H1975细胞系中验证关键生物标志物的表达;图B为通过Western blotting检测NCI-H1975细胞系和对应的正常细胞系中5个关键生物标志物蛋白的表达水平(*P<0.05,**P<0.01,***P<0.001)
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