Table_5_PRRX1 Is a Novel Prognostic Biomarker and Facilitates Tumor Progression Through Epithelial–Mesenchymal Transition in Uveal Melanoma.xlsx

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. UM develops and is sustained by inflammation and immunosuppression from the tumor microenvironment (TME). This study sought to identify a reliable TME-related biomarker that could provide survival prediction and new insight into therapy for UM patients. Based on clinical characteristics and the RNA-seq transcriptome data of 80 samples from The Cancer Genome Atlas (TCGA) database, PRRX1 as a TME- and prognosis-related gene was identified using the ESTIMATE algorithm and the LASSO–Cox regression model. A prognostic model based on PRRX1 was constructed and validated with a Gene Expression Omnibus (GEO) dataset of 63 samples. High PRRX1 expression was associated with poorer overall survival (OS) and metastasis-free survival (MFS) in UM patients. Comprehensive results of the prognostic analysis showed that PRRX1 was an independent and reliable predictor of UM. Then the results of immunological characteristics demonstrated that higher expression of PRRX1 was accompanied by higher expression of immune checkpoint genes, lower tumor mutation burden (TMB), and greater tumor cell infiltration into the TME. Gene set enrichment analysis (GSEA) showed that high PRRX1 expression correlated with angiogenesis, epithelial–mesenchymal transition (EMT), and inflammation. Furthermore, downregulation of PRRX1 weakened the process of EMT, reduced cell invasion and migration of human UM cell line MuM-2B in vitro. Taken together, these findings indicated that increased PRRX1 expression is independently a prognostic factor of poorer OS and MFS in patients with UM, and that PRRX1 promotes malignant progression of UM by facilitating EMT, suggesting that PRRX1 may be a potential target for UM therapy.

葡萄膜黑色素瘤（Uveal melanoma, UM）是成人最常见的原发性眼内恶性肿瘤。UM的发生与维持依赖于肿瘤微环境（tumor microenvironment, TME）介导的炎症反应与免疫抑制状态。本研究旨在筛选可靠的TME相关生物标志物，以期为UM患者的生存预测及治疗策略提供全新视角。研究基于癌症基因组图谱（The Cancer Genome Atlas, TCGA）数据库中80例样本的临床特征与RNA测序（RNA-seq）转录组数据，通过ESTIMATE算法及LASSO-Cox回归模型，鉴定出PRRX1为与TME及预后均相关的基因。随后构建了基于PRRX1的预后模型，并利用基因表达综合数据库（Gene Expression Omnibus, GEO）中63例样本的数据集完成验证。结果显示，PRRX1高表达与UM患者较差的总生存期（overall survival, OS）及无转移生存期（metastasis-free survival, MFS）显著相关。预后分析的综合结果表明，PRRX1是UM患者预后的独立可靠预测因子。进一步的免疫学特征分析显示，PRRX1高表达伴随免疫检查点基因高表达、较低的肿瘤突变负荷（tumor mutation burden, TMB），以及肿瘤细胞在TME中更高的浸润程度。基因集富集分析（Gene Set Enrichment Analysis, GSEA）结果显示，PRRX1高表达与血管生成、上皮间质转化（epithelial–mesenchymal transition, EMT）及炎症反应密切相关。此外，体外实验证实，下调PRRX1的表达可削弱EMT过程，并降低人UM细胞系MuM-2B的细胞侵袭与迁移能力。综上，本研究结果表明，PRRX1表达上调是UM患者较差OS和MFS的独立预后因素，且PRRX1通过促进EMT推进UM的恶性进展，提示PRRX1或可成为UM治疗的潜在靶点。