Chen Junzhe, Chen Yuezhong, Wang Liangliang, Deng Yaping, Zhou Yan, Wang Yun, Xiao Shune, Deng Chengliang
Department of Burns and Plastic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China.
The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine, Zunyi Medical University, Zunyi, Guizhou, China.
Front Immunol. 2025 Aug 13;16:1625972. doi: 10.3389/fimmu.2025.1625972. eCollection 2025.
Cancer-related lymphedema (CRL) is a common chronic complication following cancer treatment, characterized by impaired lymphatic drainage, interstitial fluid retention, and progressive fibrosis. Although the mechanisms of hypertrophic scar (HTS) fibrosis have been extensively investigated, the molecular drivers of fibrosis in CRL remain unclear. Identification of reliable biomarkers and novel therapeutic targets is essential for enabling early intervention.
Transcriptomic datasets of CRL and HTS from the Gene Expression Omnibus (GEO) were integrated to identify fibrosis-associated differentially expressed genes (DEGs) and construct co-expression modules. Weighted gene co-expression network analysis (WGCNA) and protein-protein interaction (PPI) network analysis were employed to nominate hub genes. Single-cell RNA sequencing (scRNA-seq) data were used to localize candidate gene expression within immune and mesenchymal cell populations. The most promising biomarker was validated in clinical CRL tissues by Masson's trichrome staining and Western blotting, and Pearson correlation analyses were performed to assess its association with collagen deposition and disease duration.
A total of 154 fibrosis-related genes were found to be shared by CRL and HTS. Among them, Asporin (ASPN) emerged as the most promising hub gene, with markedly elevated expression in late-stage CRL tissues. scRNA-seq analysis revealed that adipose-derived stem cells (ADSCs) were the predominant ASPN-expressing population. In CRL lesions, ASPN expression levels showed significant positive correlations with disease duration, TGF-β expression, and collagen accumulation.
ASPN is identified as a key molecular biomarker of fibrosis in CRL. Its predominant expression in ADSCs and strong association with progressive tissue remodeling suggest that ASPN holds potential as both a diagnostic indicator and a therapeutic target for CRL-related fibrosis.
癌症相关淋巴水肿（CRL）是癌症治疗后常见的慢性并发症，其特征为淋巴引流受损、间质液潴留和进行性纤维化。尽管对肥厚性瘢痕（HTS）纤维化的机制已进行了广泛研究，但CRL中纤维化的分子驱动因素仍不清楚。识别可靠的生物标志物和新的治疗靶点对于实现早期干预至关重要。
整合来自基因表达综合数据库（GEO）的CRL和HTS转录组数据集，以识别与纤维化相关的差异表达基因（DEG）并构建共表达模块。采用加权基因共表达网络分析（WGCNA）和蛋白质-蛋白质相互作用（PPI）网络分析来提名枢纽基因。利用单细胞RNA测序（scRNA-seq）数据将候选基因表达定位在免疫和间充质细胞群体中。通过Masson三色染色和蛋白质印迹法在临床CRL组织中验证最有前景的生物标志物，并进行Pearson相关性分析以评估其与胶原沉积和疾病持续时间的关联。
发现CRL和HTS共有154个与纤维化相关的基因。其中，小腱蛋白（ASPN）成为最有前景的枢纽基因，在晚期CRL组织中表达明显升高。scRNA-seq分析显示脂肪来源干细胞（ADSC）是主要表达ASPN的群体。在CRL病变中，ASPN表达水平与疾病持续时间、转化生长因子-β（TGF-β）表达和胶原积累呈显著正相关。
ASPN被确定为CRL中纤维化的关键分子生物标志物。其在ADSC中的主要表达以及与进行性组织重塑的强关联表明，ASPN作为CRL相关纤维化的诊断指标和治疗靶点具有潜力。
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