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

IF 2.8 4区医学 Q3 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

OncoTargets and therapy Pub Date : 2025-08-27 eCollection Date: 2025-01-01 DOI:10.2147/OTT.S539790

Guolin Ke, Tao Yuan, Chen Wu, Min Gao

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引用次数: 0

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=5.36×10^-¹¹), 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^-6). 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.

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CD93：光化性角化病诊断和治疗的有前途的nets相关生物标志物。

背景：光化性角化病（AK）是一种紫外线诱导的癌前皮肤状况，可能进展为皮肤鳞状细胞癌（cSCC），机制尚不明确。研究人员分析了中性粒细胞胞外陷阱（NETs）相关生物标志物，以确定关键的临床靶点。方法：利用“limma”软件包对GEO数据库中检索到的AK转录组学图谱进行分析，筛选差异表达基因（deg），并与筛选的nets相关基因集相交，提取差异表达的nets相关基因（DE-NRGs）。通过基因本体（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，确定了富集的生物过程和途径。使用LASSO回归、随机森林（RF）和支持向量机递归特征消除（SVM-RFE）筛选诊断性生物标志物，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：将AK样品与对照组进行比较，鉴定出9个DE-NRGs。GO/KEGG富集突出了中性粒细胞趋化性、迁移和IL-17信号通路。LASSO、RF和SVM-RFE选择CD93作为关键的诊断生物标志物，在训练（GSE207744， AUC=0.863）和验证（GSE32628， AUC=0.956）数据集中显示过表达。免疫组织化学证实AK皮肤与正常皮肤的CD93-MVD水平明显升高（p=5.36×10-¹¹），老年患者CD93-MVD水平升高（p=0.042），多灶性病变（p=0.028），且严重程度增加（临床：p=0.040；皮肤镜：p=0.007；病理：p=2.3×10-6）。ssGSEA显示AK免疫细胞浸润和中性粒细胞通路活性增加。分子对接鉴定Gö6976为CD93抑制剂（ΔG=-7.5 kcal/mol）。结论：我们的研究确定CD93是AK中关键的nets相关生物标志物，其机制将中性粒细胞驱动的炎症与血管生成联系起来。CD93-Gö6976相互作用为开发针对AK的新型靶向治疗提供了翻译基础。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

OncoTargets and therapy BIOTECHNOLOGY & APPLIED MICROBIOLOGY-ONCOLOGY

CiteScore

9.70

自引率

0.00%

发文量

221

审稿时长

1 months

期刊介绍： OncoTargets and Therapy is an international, peer-reviewed journal focusing on molecular aspects of cancer research, that is, the molecular diagnosis of and targeted molecular or precision therapy for all types of cancer. The journal is characterized by the rapid reporting of high-quality original research, basic science, reviews and evaluations, expert opinion and commentary that shed novel insight on a cancer or cancer subtype. Specific topics covered by the journal include: -Novel therapeutic targets and innovative agents -Novel therapeutic regimens for improved benefit and/or decreased side effects -Early stage clinical trials Further considerations when submitting to OncoTargets and Therapy: -Studies containing in vivo animal model data will be considered favorably. -Tissue microarray analyses will not be considered except in cases where they are supported by comprehensive biological studies involving multiple cell lines. -Biomarker association studies will be considered only when validated by comprehensive in vitro data and analysis of human tissue samples. -Studies utilizing publicly available data (e.g. GWAS/TCGA/GEO etc.) should add to the body of knowledge about a specific disease or relevant phenotype and must be validated using the authors’ own data through replication in an independent sample set and functional follow-up. -Bioinformatics studies must be validated using the authors’ own data through replication in an independent sample set and functional follow-up. -Single nucleotide polymorphism (SNP) studies will not be considered.