Table2_Transcriptome Profiling and Network Analysis Provide Insights Into the Pathogenesis of Vulvar Lichen Sclerosus.docx

Vulvar lichen sclerosus (VLS) is a chronic inflammatory dermatosis that affects female anogenital skin. Although VLS is considered a T cell-mediated autoimmune disease, the diagnosis criteria, molecular mechanism, and universally accepted therapies for this disease remain largely unresolved. To explore disease pathogenesis and potential biomarkers, we performed an RNA-Seq-based transcriptome analysis to profile the gene expression of VLS lesions. Differentially expressed gene (DEG) analysis revealed profound changes in expressions of coding genes, microRNAs, and long non-coding RNAs. Pathway and network analysis suggested that T cell activation-associated genes, including CD3G, CD3D, CD8B, LAT, LCK, ZAP70, CCR5, CXCR3, CXCL9, CXCL10, and CXCL11, were highly expressed in VLS, while NR4A family genes (NR4A1, NR4A2, NR4A3), whose coding products inhibit T cell activity, were significantly downregulated, suggesting heightened T cell response in VLS. Neutrophil chemoattractant genes CXCL1, CXCL2, CXCL3, CXCL8, and their cognate receptor CXCR2 were downregulated, suggesting dampened neutrophil activity. We also found the downregulation of genes involved in cell cycle progression, including cyclins (CCNB1, CCNB2, CCNL1, CCNE1, and CCNK) and centrosome factors (CENPA, CENPE, CENPF, and CENPN), while microRNA-203a and let-7, microRNAs known to inhibit cell growth, were found to be upregulated. These data collectively indicate that cell proliferation in VLS is compromised. In sum, these findings comprehensively deciphered key regulatory genes and networks in VLS, which could further our understanding of disease mechanisms and point toward therapeutic strategies.

硬化性外阴苔藓（Vulvar lichen sclerosus, VLS）是一种累及女性外阴及肛周皮肤的慢性炎症性皮肤病。尽管VLS被认为是T细胞介导的自身免疫性疾病，但目前该病的诊断标准、分子机制以及公认的治疗方案仍未完全明确。为探究该病的发病机制与潜在生物标志物，本研究开展了基于RNA测序（RNA-Seq）的转录组分析，以解析VLS病灶的基因表达谱。差异表达基因（Differentially Expressed Gene, DEG）分析显示，编码基因、微小RNA（microRNA）以及长链非编码RNA的表达均发生显著变化。通路与网络分析表明，与T细胞激活相关的基因（包括CD3G、CD3D、CD8B、LAT、LCK、ZAP70、CCR5、CXCR3、CXCL9、CXCL10及CXCL11）在VLS病灶中高表达；而编码产物可抑制T细胞活性的NR4A家族基因（NR4A1、NR4A2、NR4A3）则显著下调，提示VLS中T细胞应答增强。中性粒细胞趋化基因CXCL1、CXCL2、CXCL3、CXCL8及其同源受体CXCR2的表达下调，提示中性粒细胞活性被抑制。本研究还发现，参与细胞周期进程的基因（包括细胞周期蛋白CCNB1、CCNB2、CCNL1、CCNE1及CCNK，以及中心体因子CENPA、CENPE、CENPF及CENPN）表达下调；而已知可抑制细胞生长的miR-203a与let-7则表达上调。上述结果共同表明，VLS病灶中的细胞增殖受到抑制。综上，本研究全面解析了VLS中的关键调控基因与调控网络，有助于加深我们对该病发病机制的理解，并为治疗策略的研发指明方向。