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. 2025 Feb 20;28(2):114-130.
doi: 10.3779/j.issn.1009-3419.2025.105.01.

[FCN3 Can Serve as A Potential Biomarker for Prognosis and Immunotherapy of Lung Squamous Cell Carcinoma]

[Article in Chinese]
Wei Li  1   2   3 , Lingling Zu  1   2 , Song Xu  1   2
Affiliations

[FCN3 Can Serve as A Potential Biomarker for Prognosis and Immunotherapy of Lung Squamous Cell Carcinoma]

[Article in Chinese]
Wei Li et al. Zhongguo Fei Ai Za Zhi. .

Abstract
in English, Chinese

Background: Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide. Lung squamous cell carcinoma (LUSC) is an important pathological subtype of NSCLC. The complex immune escape mechanism limits the effectiveness of immunotherapy. Ficolin-3 (FCN3) is a crucial immunomodulatory molecule that regulates immune escape by remodeling the tumor microenvironment. However, the role of FCN3 in LUSC remains unclear. This study employed bioinformatics methods to analyze LUSC samples from The Cancer Genome Atlas (TCGA) database. The aim of this study was to explore the potential biological functions and prognostic significance of FCN3 in LUSC.

Methods: A pan-cancer analysis characterized the expression patterns and prognostic value of FCN3 across various cancer types. Simultaneously, the expression patterns of FCN3 in LUSC samples from the TCGA database and its relationship with prognosis were analyzed. The Nomogram model and somatic mutation analysis, differential expression analysis, correlation analysis, as well as Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) were constructed to explore the potential mechanisms of FCN3. Additionally, immune infiltration analysis, immune escape score (TIDE), and correlation analysis of immune-related molecules were used to reveal the regulatory role of high FCN3 levels on immunity in LUSC. Furthermore, the correlation between FCN3 expression characteristics and drug sensitivity was evaluated. Finally, in vitro experiments verified the expression characteristics of FCN3 in LUSC.

Results: The expression level of FCN3 in LUSC tissues was significantly lower than that in normal tissues. Patients with high FCN3 expression in LUSC had a poorer prognosis compared to those with low expression. Different expression levels of FCN3 were associated with the abundance of immune cell infiltration and immune cell dysfunction. It was also linked to the expression of immune checkpoints, immune stimulatory molecules, major histocompatibility complex (MHC) class molecules, and chemotherapy drug sensitivity.

Conclusions: High expression of FCN3 in LUSC is associated with poor prognosis and is linked to immune cell infiltration, immune-related pathways, and immune-related molecules. FCN3 may be a potential prognostic marker and a new target for immunotherapy in LUSC.

【中文题目：FCN3可作为肺鳞癌预后及免疫治疗 的潜在生物标志物】 【中文摘要：背景与目的 非小细胞肺癌（non-small cell lung cancer, NSCLC）是全球癌症死亡的主要原因。肺鳞状细胞癌（lung squamous cell carcinoma, LUSC）是其重要的病理组织学亚型，免疫逃逸机制复杂，使得免疫治疗的效果有限。Ficolin-3（FCN3）是一种重要的免疫调节分子，它可以通过重塑肿瘤免疫微环境来调节肿瘤的免疫逃逸，但FCN3在LUSC中的作用仍不清楚。本研究使用生物信息学方法对来自癌症基因组图谱（The Cancer Genome Atlas, TCGA）数据库的LUSC样本进行了全面分析，旨在探讨FCN3在LUSC中潜在的生物学功能以及预后意义。方法 泛癌分析表征FCN3的泛癌表达特征及预后价值，同时基于TCGA数据库中的LUSC样本数据，分析FCN3在LUSC中的表达特征及预后关系。通过构建Nomogram模型、体细胞突变分析、差异分析、相关性分析及基因本体（Gene Ontology, GO）、京都基因与基因组百科全书（Kyoto Encyclopedia of Genes and Genomes, KEGG）和基因集富集分析（Gene Set Enrichment Analysis, GSEA）进一步探索FCN3的潜在作用机制。通过免疫浸润分析、免疫逃逸评分、免疫相关分子相关性分析揭示FCN3在LUSC中高表达对免疫的调节作用，同时评估FCN3特征表达与药物敏感性的相关性。体外实验验证FCN3在LUSC中的表达特征。结果 FCN3在LUSC组织中的表达水平显著低于正常组织。高表达FCN3的LUSC患者预后较差。FCN3的不同表达情况与免疫细胞浸润丰度、免疫细胞功能障碍有关联，并且与免疫检查点、免疫刺激分子、主要组织相容性复合体（major histocompatibility complex, MHC）类分子表达及化疗药物敏感性也存在关联。结论 LUSC中FCN3的高表达与不良预后有关，并且FCN3与免疫细胞浸润、相关免疫通路及免疫相关分子有关，FCN3可能是LUSC潜在的预后标志物和免疫治疗新靶点。 】 【中文关键词：FCN3；肺肿瘤；免疫；生物标志物】.

Keywords: Biomarker; FCN3; Immunity; Lung neoplasms.

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Conflict of interest statement

Competing interests: The authors declare that they have no competing interests.

Figures

Fig 1
图1. FCN3的泛癌分析。A：FCN3在不同类型肿瘤中的差异表达，FCN3在LUSC中低表达；B：FCN3在不同肿瘤中的免疫浸润情况；C：森林图可视化展示FCN3表达对OS的影响；D：森林图可视化展示FCN3表达对DSS的影响。*P<0.05，**P<0.01，***P<0.001。
Fig 2
图2. FCN3在LUSC中的预后和ROC曲线分析以及FCN3表达与LUSC不同临床特征的相关性。A：FCN3在LUSC的表达情况；B：根据FCN3表达水平绘制的LUSC患者的Kaplan-Meier图；C：在不同性别中FCN3表达差异；D-F：在肿瘤的TNM分期中，FCN3与 T（肿瘤）和N（淋巴结）和 M（转移）均相关。***P<0.05。
Fig 3
图3. 构建LUSC患者1、3、5年生存预后Nomogram模型。A：构建Nomogram模型；B：用于预测LUSC中1、3和5年OS列线图的ROC曲线; C：用于预测LUSC中1、3和5年OS的列线图校准曲线。
Fig 4
图4. FCN3的高低表达在LUSC中的体细胞突变分析。A：FCN3高低表达组的TMB差异；B：低表达组突变频率最高的前20个基因；C：高表达组突变频率最高的前20个基因。***P<0.001。
Fig 5
图5. 鉴定LUSC中与FCN3功能相关的枢纽基因，并进行GO/KEGG富集分析和GSEA分析。A：火山图展示TCGA数据库分析的LUSC中与FCN3表达水平相关的DEGs；B：热图可视化展示FCN3表达的差异基因；C：GO和KEGG通路富集分析；D：对DEGs基因GSEA富集分析，这些基因在多个生物学通路中显著富集。
Fig 6
图6. FCN3高相关性基因鉴定和通路富集。A：热图可视化与FCN3基因表达显著相关的分子；B：使用STRING数据库构建FCN3的蛋白关系网络；C：FCN3高相关性基因的GSEA富集分析（NSE为正值）；D：FCN3高相关性基因的GSEA富集分析（NSE为负值）。
Fig 7
图7. FCN3的表达与免疫浸润和免疫治疗反应的相关性。A：采用ESTIMATE算法评估LUSC样本的免疫浸润情况；B：TIDE免疫评分与FCN3表达的关系；C，D：利用ssGSEA可视化24种免疫细胞标志性基因，展示FCN3高低表达组中的免疫浸润情况。**P<0.01，***P<0.001。
Fig 8
图8. LUSC中FCN3的表达与免疫检查点分子相关性。A：LUSC中FCN3高低表达组中免疫检查点分子表达的差异；B：FCN3与PDCD1、CD274、CTLA4和TIGIT表达量的相关性分析。**P<0.01，***P<0.001。
Fig 9
图9. LUSC中FCN3的表达与免疫刺激分子相关性。A：LUSC中FCN3高低表达组中免疫刺激分子表达的差异；B：FCN3与IL6、CXCR4、CD27和CD86表达量的相关性分析。*P<0.05，**P<0.01，***P<0.001。
Fig 10
图10. LUSC中FCN3的表达与MHC分子相关性。A：LUSC中FCN3高低表达组中MHC分子表达的差异；B：FCN3与MHC-DMA、HLA-DOA、HLA-DPA1和HLA-DRA表达量的相关性分析。*P<0.05，***P<0.001。
Fig 11
图11. FCN3表达与药物敏感性的相关性分析（P<0.05）。A：紫杉醇； B：放线菌素D；C：Sepantronium bromide；D：Eg5_9814；E：多西他赛；F：达珀利奈；G：长春瑞滨；H：AZD8055；I：托泊替康。
Fig 12
图12. 体外实验验证FCN3在LUSC的表达。A：LUSC细胞系中FCN3的mRNA表达水平；B：FCN3在正常肺组织和LUSC中的免疫组化染色结果。染色使用了抗体CAB025945，展示了FCN3在这两种组织中的表达差异。图片来源：Human Protein Atlas，访问链接： https://www.proteinatlas.org/；C：LUSC细胞系中FCN3的蛋白表达水平。
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