Keratin gene signature expression drives epithelial-mesenchymal transition through enhanced TGF-β signaling pathway activation and correlates with adverse prognosis in lung adenocarcinoma

作者全名："Li, Gang; Guo, Jinbao; Mou, Yunfei; Luo, Qingsong; Wang, Xuehai; Xue, Wei; Hou, Ting; Zeng, Tianyang; Yang, Yi"

作者地址："[Li, Gang; Luo, Qingsong; Wang, Xuehai] Univ Elect Sci & Technol China, Sichuan Acad Med Sci, Dept Thorac Surg, Chengdu 610072, Peoples R China; [Li, Gang; Luo, Qingsong; Wang, Xuehai] Univ Elect Sci & Technol China, Sichuan Peoples Hosp, Chengdu 610072, Peoples R China; [Guo, Jinbao; Zeng, Tianyang] Chongqing Med Univ, Affiliated Hosp 1, Dept Cardiothorac Surg, Chongqing 400016, Peoples R China; [Mou, Yunfei; Xue, Wei; Yang, Yi] Chengdu Third Peoples Hosp, Dept Thorac Surg, Chengdu 610082, Peoples R China; [Hou, Ting] Burning Rock Biotech, Guangzhou 510300, Peoples R China"

通信作者："Zeng, TY (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Dept Cardiothorac Surg, Chongqing 400016, Peoples R China.; Yang, Y (通讯作者)，Chengdu Third Peoples Hosp, Dept Thorac Surg, Chengdu 610082, Peoples R China."

来源：HELIYON

ESI学科分类：　

WOS号：WOS:001179465600001

JCR分区：Q1

影响因子：3.4

年份：2024

卷号：10

期号：3

开始页：　

结束页：　

文献类型：Article

关键词：Lung adenocarcinoma (LUAD); Keratins; Prognosis; TGF; beta signaling; WNT; beta catenin signaling; EMT; Drug sensitivity

摘要："<bold>Background: </bold>Lung adenocarcinoma (LUAD) stands as the foremost histological subtype of non-small-cell lung cancer, accounting for approximately 40% of all lung cancer diagnoses. However, there remains a critical unmet need to enhance the prediction of clinical outcomes and therapy responses in LUAD patients. Keratins (KRTs), serving as the structural components of the intermediate filament cytoskeleton in epithelial cells, play a crucial role in the advancement of tumor progression. This study investigated the prognostic significance of the KRT family gene and developed a KRT gene signature (KGS) for prognostic assessment and treatment guidance in LUAD. <bold>Methods: </bold>Transcriptome profiles and associated clinical details of LUAD patients were meticulously gathered from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The KGS score was developed based on the expression of five prognostic KRT genes (KRT7, KRT8, KRT17, KRT18, and KRT80), and the upper quartile of the KGS score was chosen as the cutoff. The Kaplan-Meier method was evaluated to compare survival outcomes between KGS-high and KGS-low groups. The underlying mechanism was further investigated by GSEA, GSVA, and other bioinformatic algorithms. <bold>Results: </bold>High expression of the KGS signature exhibited a robust association with poorer overall survival (OS) in the TCGA-LUAD dataset (HR: 1.81; 95% CI: 1.35-2.42, P = 0.00011). The association was further corroborated in three external GEO cohorts, including GSE31210 (HR: 3.31; 95% CI: 1.7-6.47, P = 0.00017), GSE72094 (HR: 1.95; 95% CI: 1.34-2.85, P = 0.00057) and GSE26939 (HR: 3.19; 95% CI: 1.74-5.84, P < 0.0001). Interestingly, KGS-high tumors revealed enrichments in TGF-beta and WNT-beta catenin signaling pathways, exhibited heightened activation of the epithelial-mesenchymal transition (EMT) pathway and proved intensified tumor stemness compared to their KGS-low counterparts. Additionally, KGS-high tumor cells exhibited increased sensitivity to several targeted agents, including gefitinib, erlotinib, lapatinib, and trametinib, in comparison to KGS-low cells. <bold>Conclusion: </bold>This study developed a KGS score that independently predicts the prognosis in LUAD. High expression of KGS score, accompanied by upregulation of TGF-beta and WNT-beta catenin signaling pathways, confers more aggressive EMT and tumor progression."

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