S100A4和VEGF在银屑病中的作用及其通过低聚半乳糖调控的机制研究  

Role of S100A4 and vascular endothelial growth factor(VEGF)in psoriasis and its mechanism of regulation by galactose oligogalactans(GOS)

作　　者：许浩然 张倩[1] 王祯瑞 王慧琴[2] 吴卫东[2,3] XU Haoran;ZHANG Qian;WANG Zhenrui;WANG Huiqin;WU Weidong(Department of Medicine,Shihezi University,Shihezi Xinjiang 832000,China;Research and Management Center,People′s Hospital of Xinjiang Uygur Autonomous Region;Department of Dermatology and Venereology,People′s Hospital of Xinjiang Uygur Autonomous Region,Urumqi 830001,China)

机构地区：[1]石河子大学医学部,新疆石河子832000 [2]新疆维吾尔自治区人民医院科研管理中心 [3]新疆维吾尔自治区人民医院皮肤性病科,乌鲁木齐830001

出　　处：《新疆医科大学学报》2025年第4期447-455,共9页Journal of Xinjiang Medical University

基　　金：新疆维吾尔自治区自然科学基金项目(2023D01C73);新疆维吾尔自治区自然科学基金重点项目(2022D01D52)。

摘　　要：目的探究S100钙结合蛋白A4(S100A4)调控的潜在靶标基因及其功能,以及S100A4和血管内皮生长因子(Vascular endothelial growth factor,VEGF)在咪喹莫特诱导的银屑病小鼠模型中的表达。评估低聚半乳糖(Galacto-oligasuccharides,GOS)对S100A4和VEGF表达的影响,考察GOS对改善银屑病样皮炎症状的潜在疗效。方法在HaCat细胞中进行传代培养,并使用转录组测序技术研究S100A4沉默后的基因表达模式。选取7~8周龄健康的野生型雄性Balb/c小鼠,分为凡士林(VAS)组、咪喹莫特(IMQ)组、低聚半乳糖(GOS)组、生理盐水(NS)组,每组11只,IMQ组、GOS组、NS组每日涂抹IMQ乳膏建立银屑病小鼠模型,VAS组给予同等剂量的凡士林乳膏,持续1周。建模成功后,GOS组灌喂低聚半乳糖,800 mg·kg-1·d-1,NS组每日灌喂同等剂量的生理盐水,持续2周,VAS组、IMQ组小鼠背部外用0.9%生理盐水,1次/d,持续2周,期间定期观察小鼠皮损情况,于第21天处死小鼠,通过HE染色观察皮损病理表现,Western印迹及实时荧光定量PCR(RT-qPCR)检测S100A4及VEGF的表达。结果沉默S100A4引起的显著差异表达基因(DEGs)有747个,其中上调表达基因345个,下调表达基因402个。富集分析揭示上调的DEGs主要富集在炎症应答、角质化等通路,下调的DEGs主要富集在多细胞生物生长、血管生成等通路。动物实验显示,GOS组小鼠的鳞屑、红斑明显改善。Western印迹结果显示,IMQ组S100A4(P=0.012)、VEGF(P=0.004)蛋白表达均较VAS组升高,GOS组S100A4(P=0.011)、VEGF(P=0.015)蛋白表达均较NS组下降;RT-qPCR显示,IMQ组S100A4 mRNA(P=0.009)表达量较VAS组升高,GOS组S100A4 mRNA(P=0.045)表达量较NS组显著降低。结论S100A4可以调控与炎症和血管生成相关的多个基因的表达,调节细胞凋亡功能通路相关基因的可变剪接;S100A4及VEGF在银屑病小鼠模型中呈高表达;GOS可以通过抑制S100A4及VEGF的表达,显著改善IMQ诱导的小鼠银屑病样皮炎。Objective To explore the potential target genes regulated by S100A4 and their functions and to investigate the expression of S100A4 and vascular endothelial growth factor(VEGF)in imiquimod-induced psoriasis mouse model.To assess the effect of oligogalactose(GOS)on S100A4 and VEGF expression,and to examine the potential efficacy of GOS in ameliorating the symptoms of psoriasis-like dermatitis.Methods Passage cultures were performed in HaCat cells and transcriptome sequencing was used to study gene expression patterns after S100A4 silencing.Healthy wild-type male Balb/c mice at 7-8 weeks of age were selected and divided into Vaseline(VAS),imiquimod(IMQ),oligogalactose(GOS)and saline(NS)groups,with 11 mice in each group.IMQ,GOS and NS groups were coated with IMQ cream daily to establish a mouse model of psoriasis,and the VAS group was given the same dosage of Vaseline ointment for 1 week.After successful modelling,the GOS group was fed with oligogalactose at 800 mg·kg-1·d-1,the NS group was fed with saline at the same dose daily for 2 weeks,and the VAS and IMQ groups were given 0.9%saline on the back of the mice once/d for 2 weeks,during which the mice were observed regularly for the lesions,and then the mice were executed on day 21,and the pathological manifestations of the skin lesions were observed by HE staining,and the expression of S100A4 and VEGF was detected by Western blotting and real-time fluorescence quantitative PCR(RT-qPCR).Results The number of differentially expressed genes(DEGs)induced by silencing of S100A4 was 747,including 345 up-regulated genes and 402 down-regulated genes.Enrichment analysis revealed that the up-regulated DEGs were mainly enriched in the pathways of inflammatory response and keratinisation,and the down-regulated DEGs were mainly enriched in the pathways of multicellular biological growth and angiogenesis.Animal experiments showed that scales and erythema were significantly improved in the GOS group.Western blotting results showed that the expression of S100A4(P=0.012)and VEGF

关 键 词：银屑病 咪喹莫特模型 低聚半乳糖 RNA-SEQ S100钙结合蛋白A4 血管内皮生长因子 

分 类 号：R758.63[医药卫生—皮肤病学与性病学]