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已发表论文
基于整体和单细胞转录组学的肝细胞癌中神经内分泌肿瘤相关基因的预后特征
Authors Lu N, Gu Z, Yuan X, Jin R, Li J
Received 11 June 2025
Accepted for publication 26 September 2025
Published 15 October 2025 Volume 2025:12 Pages 2351—2367
DOI https://doi.org/10.2147/JHC.S546404
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 3
Editor who approved publication: Dr Mohamed Shaker
Ningning Lu,1,* Zhixia Gu,2– 5,* Xiaoxue Yuan,2– 5 Ronghua Jin,2– 5 Jianjun Li1
1Interventional Therapy Center for Oncology, Beijing You’an Hospital, Capital Medical University, Beijing, 100015, People’s Republic of China; 2National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, People’s Republic of China; 3Beijing Institute of Infectious Diseases, Beijing, 100015, People’s Republic of China; 4National Center for Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, People’s Republic of China; 5Beijing Key Laboratory of Emerging Infectious Diseases, Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Ronghua Jin; Jianjun Li, Email ronghuajin@ccmu.edu.cn; ljjir@ccmu.edu.cn
Background: Inflammation drives tumor development, with neutrophil extracellular traps (NETs) promoting progression through metastasis, immune suppression, and microenvironment modulation. However, the role of NETs-related genes in hepatocellular carcinoma (HCC) immunity response is still unclear.
Methods: We integrated single-cell RNA sequencing (GSE202642, seven tumor samples and four normal liver samples) and The Cancer Genome Atlas (TCGA, n=312) transcriptomic data to identify NETs-related gene signatures. Weighted gene co-expression network analysis (WGCNA) identified NETs-correlated gene modules, and LASSO-COX regression selected prognostic genes for risk stratification. A nomogram was developed to predict survival, while functional, mutation, immune, and drug sensitivity analyses highlighted intergroup differences. EdU and CCK-8 cell proliferation assays confirmed the role of NETs-related genes in HCC cell proliferation.
Results: The analysis revealed significant differences in survival time between high- and low-NETs groups. GAS2L3 and RTN3 were identified and validated as independent prognostic factors. ROC and decision curve analysis (DCA) demonstrated that the nomogram model combining NETs risk scores with clinical parameters exhibited robust prognostic performance. The high-risk subgroup was enriched in glycosphingolipid biosynthesis pathways and showed higher mutati843on rates, especially in TP53, CTNNB1, and MUC16, along with overexpression of immunosuppressive genes (VTCN1, LAIR1). In vitro experiments confirmed that GAS2L3 knockdown inhibited HepG2 and Huh7 cell proliferation.
Conclusion: Integrated multi-omics analysis revealed NETs-associated prognostic signatures in HCC, with GAS2L3 identified as a key gene linking NETs to tumor progression and therapeutic potential.
Keywords: hepatocellular carcinoma, single-cell RNA sequencing, NETs-related genes, GAS2L3, immune infiltration, prognostic model
1Interventional Therapy Center for Oncology, Beijing You’an Hospital, Capital Medical University, Beijing, 100015, People’s Republic of China; 2National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, People’s Republic of China; 3Beijing Institute of Infectious Diseases, Beijing, 100015, People’s Republic of China; 4National Center for Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, People’s Republic of China; 5Beijing Key Laboratory of Emerging Infectious Diseases, Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Ronghua Jin; Jianjun Li, Email ronghuajin@ccmu.edu.cn; ljjir@ccmu.edu.cn
Background: Inflammation drives tumor development, with neutrophil extracellular traps (NETs) promoting progression through metastasis, immune suppression, and microenvironment modulation. However, the role of NETs-related genes in hepatocellular carcinoma (HCC) immunity response is still unclear.
Methods: We integrated single-cell RNA sequencing (GSE202642, seven tumor samples and four normal liver samples) and The Cancer Genome Atlas (TCGA, n=312) transcriptomic data to identify NETs-related gene signatures. Weighted gene co-expression network analysis (WGCNA) identified NETs-correlated gene modules, and LASSO-COX regression selected prognostic genes for risk stratification. A nomogram was developed to predict survival, while functional, mutation, immune, and drug sensitivity analyses highlighted intergroup differences. EdU and CCK-8 cell proliferation assays confirmed the role of NETs-related genes in HCC cell proliferation.
Results: The analysis revealed significant differences in survival time between high- and low-NETs groups. GAS2L3 and RTN3 were identified and validated as independent prognostic factors. ROC and decision curve analysis (DCA) demonstrated that the nomogram model combining NETs risk scores with clinical parameters exhibited robust prognostic performance. The high-risk subgroup was enriched in glycosphingolipid biosynthesis pathways and showed higher mutati843on rates, especially in TP53, CTNNB1, and MUC16, along with overexpression of immunosuppressive genes (VTCN1, LAIR1). In vitro experiments confirmed that GAS2L3 knockdown inhibited HepG2 and Huh7 cell proliferation.
Conclusion: Integrated multi-omics analysis revealed NETs-associated prognostic signatures in HCC, with GAS2L3 identified as a key gene linking NETs to tumor progression and therapeutic potential.
Keywords: hepatocellular carcinoma, single-cell RNA sequencing, NETs-related genes, GAS2L3, immune infiltration, prognostic model