Wang Yu, Jiang Tao, Lin Ziyou, Dai Peijun, Wei Wenxin, Dong Chengyuan, Zhang Xuelin, Zhang Zhifeng
Department of Hepatic Surgery, Third Affiliated Hospital of Naval Medical University, Shanghai, China.
Department of orthopedics, Third Affiliated Hospital of Naval Medical University, Shanghai, China.
J Cancer. 2025 Jun 23;16(9):2984-2996. doi: 10.7150/jca.111751. eCollection 2025.
The speckle-type POZ protein (SPOP) has emerged as an important regulator of protein degradation in various cancers. However, the precise role of SPOP in lung adenocarcinoma (LUAD) remains unclear, particularly in relation to its expression patterns, prognostic significance, and potential as a therapeutic target. This study aimed to investigate the expression, prognostic value, and biological functions of SPOP in LUAD, and to explore its potential as a biomarker for personalized treatment strategies. We performed a comprehensive analysis of SPOP expression using multiple public datasets, including TCGA, TCGA-GTEx, and GEO. Survival analyses were conducted through Cox regression and Kaplan-Meier methods to assess the prognostic significance of SPOP in LUAD. Gene Set Variation Analysis (GSVA) and Gene Set Enrichment Analysis (GSEA) were employed to uncover biological pathways associated with SPOP expression. Immune microenvironment analysis and drug sensitivity data from the GDSC database were used to explore the potential role of SPOP in immune modulation and therapeutic response. The biological role of SPOP in LUAD was further explored through molecular docking analysis and experimental validation. SPOP expression was significantly reduced in LUAD compared to normal tissues, with lower expression correlating with poor overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI). Cox regression analysis confirmed that SPOP is an independent prognostic factor for LUAD. Functional analyses revealed that low SPOP expression was associated with disrupted immune regulation and altered metabolic pathways, potentially driving tumor progression. Immune profiling identified significant correlations between SPOP expression and immune cell recruitment, inflammatory signaling, and LUAD subtypes. Drug sensitivity analysis suggested that low SPOP expression is linked to increased sensitivity to zibotentan and 5-fluorouracil. Additionally, molecular docking analysis revealed key interaction sites between SPOP and NANOG, and SPOP knockdown in A549 and T24 cells resulted in downregulation of immune markers CD47 and CD155. SPOP is a reliable independent prognostic biomarker in LUAD, influencing tumor progression, immune microenvironment, and therapeutic response. Our findings support the potential of SPOP as a novel therapeutic target for personalized treatment strategies in LUAD.
斑点型POZ蛋白（SPOP）已成为多种癌症中蛋白质降解的重要调节因子。然而，SPOP在肺腺癌（LUAD）中的具体作用仍不清楚，尤其是其表达模式、预后意义以及作为治疗靶点的潜力。本研究旨在调查SPOP在LUAD中的表达、预后价值和生物学功能，并探索其作为个性化治疗策略生物标志物的潜力。我们使用多个公共数据集，包括TCGA、TCGA-GTEx和GEO，对SPOP表达进行了全面分析。通过Cox回归和Kaplan-Meier方法进行生存分析，以评估SPOP在LUAD中的预后意义。采用基因集变异分析（GSVA）和基因集富集分析（GSEA）来揭示与SPOP表达相关的生物学途径。利用免疫微环境分析和来自GDSC数据库的药物敏感性数据，探索SPOP在免疫调节和治疗反应中的潜在作用。通过分子对接分析和实验验证，进一步探究了SPOP在LUAD中的生物学作用。与正常组织相比，LUAD中SPOP表达显著降低，较低的表达与较差的总生存期（OS）、疾病特异性生存期（DSS）和无进展生存期（PFI）相关。Cox回归分析证实，SPOP是LUAD的独立预后因素。功能分析表明，低SPOP表达与免疫调节紊乱和代谢途径改变有关，可能驱动肿瘤进展。免疫谱分析确定了SPOP表达与免疫细胞募集、炎症信号和LUAD亚型之间的显著相关性。药物敏感性分析表明，低SPOP表达与对齐考诺肽和5-氟尿嘧啶的敏感性增加有关。此外，分子对接分析揭示了SPOP与NANOG之间的关键相互作用位点，在A549和T24细胞中敲低SPOP导致免疫标志物CD47和CD155下调。SPOP是LUAD中可靠的独立预后生物标志物，影响肿瘤进展、免疫微环境和治疗反应。我们的研究结果支持SPOP作为LUAD个性化治疗策略新治疗靶点的潜力。
