CD93：一种用于光化性角化病诊断和治疗的有前景的与中性粒细胞胞外陷阱相关的生物标志物。

CD93: A Promising NETs-Related Biomarker for Diagnosis and Therapy in Actinic Keratosis.

作者信息

Ke Guolin, Yuan Tao, Wu Chen, Gao Min

机构信息

Department of Dermatology, The First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, 230032, People's Republic of China.

Department of Dermatology and Venereology, The First Affiliated Hospital, Wannan Medical College, Wuhu, Anhui, 241001, People's Republic of China.

出版信息

Onco Targets Ther. 2025 Aug 27;18:935-951. doi: 10.2147/OTT.S539790. eCollection 2025.

DOI:10.2147/OTT.S539790

PMID:40901493

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12400581/

Abstract

BACKGROUND

Actinic keratosis (AK), a UV-induced precancerous skin condition potentially progressing to cutaneous squamous cell carcinoma (cSCC) with undefined mechanisms, was analyzed for neutrophil extracellular traps (NETs)-related biomarkers to identify key clinical targets.

METHODS

Transcriptomic profiles of AK retrieved from the GEO database were analyzed using the "limma" package to screen differentially expressed genes (DEGs), which were intersected with a curated NETs-related gene set to extract differentially expressed NETs-related genes (DE-NRGs). Functional enrichment analyses via Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) annotations identified enriched biological processes and pathways. Diagnostic biomarkers were screened using LASSO regression, random forest (RF), and Support Vector Machine Recursive Feature Elimination (SVM-RFE), with performance assessed by receiver operating characteristic (ROC) curves. Clinical validation compared CD93-positive microvessel density (CD93-MVD) levels between 53 AK samples and normal skin controls. Single-sample gene set enrichment analysis (ssGSEA) evaluated immune cell infiltration and neutrophil-related pathway activity, while molecular docking screened potential CD93-targeting drugs.

RESULTS

Nine DE-NRGs were identified by comparing AK samples with controls. GO/KEGG enrichment highlighted neutrophil chemotaxis, migration, and IL-17 signaling pathways. LASSO, RF, and SVM-RFE selected CD93 as a key diagnostic biomarker, showing overexpression in training (GSE207744, AUC=0.863) and validation (GSE32628, AUC=0.956) datasets. Immunohistochemistry confirmed significantly higher CD93-MVD levels between AK and normal skin (p=5.36×10¹¹), with elevation in elderly patients (p=0.042), multifocal lesions (p=0.028), and with increasing severity (clinical: p=0.040; dermoscopic: p=0.007; pathological: p=2.3×10). ssGSEA revealed increased immune cell infiltration and neutrophil pathway activity in AK. Molecular docking identified Gö6976 as a CD93 inhibitor (ΔG=-7.5 kcal/mol).

CONCLUSION

Our study establishes CD93 as a key NETs-related biomarker in AK, mechanistically linking neutrophil-driven inflammation to angiogenesis. The CD93-Gö6976 interaction provides a translational basis for developing novel targeted therapies against AK.

摘要

背景

光化性角化病（AK）是一种紫外线诱导的癌前皮肤疾病，可能进展为皮肤鳞状细胞癌（cSCC），但其机制尚不明确。本研究分析了与中性粒细胞胞外陷阱（NETs）相关的生物标志物，以确定关键的临床靶点。

方法

使用“limma”软件包分析从基因表达综合数据库（GEO）检索到的AK转录组谱，以筛选差异表达基因（DEGs），并将其与精心策划的NETs相关基因集进行交叉分析，以提取差异表达的NETs相关基因（DE-NRGs）。通过基因本体论（GO）和京都基因与基因组百科全书（KEGG）注释进行功能富集分析，以确定富集的生物学过程和途径。使用套索回归、随机森林（RF）和支持向量机递归特征消除（SVM-RFE）筛选诊断生物标志物，并通过受试者工作特征（ROC）曲线评估其性能。临床验证比较了53例AK样本和正常皮肤对照之间的CD93阳性微血管密度（CD93-MVD）水平。单样本基因集富集分析（ssGSEA）评估免疫细胞浸润和中性粒细胞相关途径活性，而分子对接筛选潜在的CD93靶向药物。

结果

通过比较AK样本与对照，鉴定出9个DE-NRGs。GO/KEGG富集分析突出了中性粒细胞趋化、迁移和IL-17信号通路。套索回归、RF和SVM-RFE选择CD93作为关键诊断生物标志物，在训练数据集（GSE207744，AUC=0.863）和验证数据集（GSE32628，AUC=0.956）中均显示过表达。免疫组织化学证实，AK与正常皮肤之间的CD93-MVD水平显著更高（p=5.36×10¹¹），老年患者（p=0.042）、多灶性病变（p=0.028）以及病情严重程度增加时（临床：p=0.040；皮肤镜检查：p=0.007；病理：p=2.3×10）CD93-MVD水平升高。ssGSEA显示AK中免疫细胞浸润和中性粒细胞途径活性增加。分子对接确定Gö6976为CD93抑制剂（ΔG=-7.5 kcal/mol）。