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International journal of biological macromolecules. 2025 Jun 10:145149. doi: 10.1016/j.ijbiomac.2025.145149 Q17.72024

Transcriptome-wide gene-age interaction study and multi-omics comprehensive analysis reveals heterogeneous regulation of NLRC4 during aging on HNSCC prognosis and immune microenvironment

转录组基因年龄交互作用研究及多组学综合分析揭示了NLRC4在衰老过程中对头颈部鳞癌预后和免疫微环境的异质性调控 翻译改进

Ziang Xu  1, Maojie Xue  2, Yuqing Yang  2, Xiaoshuang Xu  2, Xiang Wang  2, Moxu Wang  3, Tao Liu  3, Zhixuan Liu  3, Hua Yuan  4, Wei Zhang  5, Ruyang Zhang  6

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作者单位

  • 1 State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University, Nanjing, Jiangsu 210029, China; Department of the Ninth Outpatient, Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China.
  • 2 Department of Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
  • 3 State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University, Nanjing, Jiangsu 210029, China; Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
  • 4 State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University, Nanjing, Jiangsu 210029, China; Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, Jiangsu 210029, China. Electronic address: yuanhua@njmu.edu.cn.
  • 5 State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University, Nanjing, Jiangsu 210029, China; Department of Oral Special Consultation, Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China. Electronic address: zhangwei0508@njmu.edu.cn.
  • 6 Department of Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China; China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China; Changzhou Medical Center, Nanjing Medical University, Changzhou, Jiangsu 213164, China; Information Center, The Second People's Hospital of Changzhou, the Third Affiliated Hospital of Nanjing Medical University, Changzhou, Changzhou, Jiangsu 213164, China. Electronic address: zhangruyang@njmu.edu.cn.

    • DOI: 10.1016/j.ijbiomac.2025.145149 PMID: 40499851

    摘要 中英对照阅读

    Substantial age-related heterogeneity exists in the treatment of head and neck squamous cell carcinoma (HNSCC) patients, effective predictive guidance is needed to improve survival of elderly HNSCC patients, but it is unclear whether the effect of gene expression on HNSCC overall survival varies with age. By integrating transcriptome data from multiple centers, we identified one gene, NLRC4, whose effect was significantly modified by age on a transcriptome-wide scale (HRTCGA = 1.025, P = 8.50 × 10-05, FDR-q = 8.78 × 10-03; HRGEO = 1.035, P = 2.39 × 10-06, FDR-q = 1.41 × 10-02; HRcombined = 1.029, P = 4.96 × 10-09, HRArrayExpress = 1.052, P = 1.51 × 10-02). Moreover, there was an antagonistic interaction between NLRC4 low expression and aging. Comprehensive analysis using multi-omics data suggested that immune-related indicators showed varying degrees of differences in NLRC4-age subgroups, NLRC4 was highly expressed in monocytes/macrophages, and may associated with M1/M2 macrophage polarization. Subsequent transcriptome-wide NLRC4-age-based three-way interaction analysis reflected the broad association among NLRC4, age and ECM-related genes (mainly the collagen family) on the prognosis of HNSCC. Identified three-way interactions can better improve prognostic accuracy than two-way interactions. Our research identified the complex interaction effects among multiple environment and transcriptomic factors, and provided therapeutic target for HNSCC patients.

    Keywords: Gene-age interaction; Head and neck squamous cell carcinoma; Immune landscape; Macrophage polarization; Overall survival; Three-way interaction.

    Keywords：transcriptome-wide gene; age interaction; heterogeneous regulation; NLRC4; immune microenvironment

    在头颈部鳞状细胞癌（HNSCC）患者的治疗中存在显著的年龄相关异质性，有效的预测指导对于改善老年 HNSCC 患者的生存率至关重要，但尚不清楚基因表达对 HNSCC 总体生存的影响是否会随着年龄而变化。通过整合来自多个中心的转录组数据，我们发现一个基因 NLRC4，在转录组水平上其作用因年龄而显著改变（TCGA 的 HR = 1.025, P = 8.50 × 10-05, FDR-q = 8.78 × 10-03；GEO 的 HR = 1.035, P = 2.39 × 10-06, FDR-q = 1.41 × 10-02; 综合的 HR = 1.029, P = 4.96 × 10-09，ArrayExpress 的 HR = 1.052, P = 1.51 × 10-02）。此外，在 NLRC4 表达较低的患者中与衰老之间存在拮抗作用。使用多组学数据进行全面分析表明，免疫相关指标在不同年龄亚组中的 NLRC4 中表现出不同程度的差异，NLRC4 在单核细胞/巨噬细胞中高表达，并且可能与 M1/M2 巨噬细胞极化有关。后续基于转录组水平上 NLRC4-年龄的基础三向交互分析反映了 NLRC4、年龄和 ECM 相关基因（主要是胶原蛋白家族）在 HNSCC 预后中的广泛关联。所识别的三重相互作用比二元相互作用更能提高预后的准确性。我们的研究确定了多个环境和转录组因素之间的复杂交互效应，并为 HNSCC 患者的治疗提供了靶点。

    关键词： 基因-年龄交互；头颈部鳞状细胞癌；免疫图谱；巨噬细胞极化；总体生存率；三向交互。

    关键词：转录组范围内的基因; 年龄互作; 异质性调控; NLRC4; 免疫微环境

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    期刊名：International journal of biological macromolecules

    缩写：INT J BIOL MACROMOL

    ISSN：0141-8130

    e-ISSN：1879-0003

    IF/分区：7.7/Q1

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