Zhu Shuting, Zhu Rui, Wang Yanna, Zhu Junru, Zong Yifan, Zhu Liucun, Guo Wenna
School of Life Sciences, Zhengzhou University, Zhengzhou, China.
Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China.
Sci Rep. 2025 Mar 19;15(1):9486. doi: 10.1038/s41598-025-93695-x.
Cutaneous melanoma (CM) is an aggressive skin cancer with high metastatic potential and poor prognosis. Splicing factors, which regulate pre-mRNA alternative splicing (AS) events, have been suggested as potential therapeutic targets in CM. The objective of this study was to identify candidate splicing factors involved in CM through a systems biology approach and to elucidate their roles in CM progression. 390 AS events associated with patient survival were identified using bivariate Cox regression and receiver operating characteristic (ROC) analyses. 121 splicing factors significantly associated with patient prognosis were screened by univariate Cox regression analysis. A bipartite association network between AS events and splicing factors was constructed using Spearman correlation analysis. Based on the network topology, five candidate splice factors were identified. Among them, U2SURP, a poorly characterized serine/arginine-rich protein family member, was selected for further analysis in CM. Results indicated that U2SURP gene expression was significantly negatively correlated with the Immune Infiltration Score, the infiltration levels of dendritic cells, gamma-delta T cells, natural killer (NK) cells, and cytotoxic cells, as well as the expression of the immune checkpoint gene PD-1, suggesting that U2SURP may serve as a potential target for CM immunotherapy. Experimental validation showed that U2SURP mRNA and protein were overexpressed in CM cells, and silencing of U2SURP using siRNA significantly reduced CM cell survival, proliferation and migration. Furthermore, single-cell functional analysis showed that U2SURP gene expression was positively correlated with CM cell proliferation and differentiation. This study systematically identified candidate splicing factors involved in CM and provided new insights into the role of U2SURP in CM progression. These findings contribute to a deeper understanding of the pathogenesis of CM and establish new approaches for identifying splicing-related cancer therapeutic targets.
皮肤黑色素瘤（CM）是一种侵袭性皮肤癌，具有高转移潜能且预后较差。剪接因子可调节前体mRNA可变剪接（AS）事件，已被认为是CM潜在的治疗靶点。本研究的目的是通过系统生物学方法鉴定参与CM的候选剪接因子，并阐明它们在CM进展中的作用。使用双变量Cox回归和受试者工作特征（ROC）分析，确定了390个与患者生存相关的AS事件。通过单变量Cox回归分析筛选出121个与患者预后显著相关的剪接因子。利用Spearman相关分析构建了AS事件与剪接因子之间的二分关联网络。基于网络拓扑结构，确定了五个候选剪接因子。其中，U2SURP是一个特征不明确的富含丝氨酸/精氨酸的蛋白质家族成员，被选择在CM中进行进一步分析。结果表明，U2SURP基因表达与免疫浸润评分、树突状细胞、γδT细胞、自然杀伤（NK）细胞和细胞毒性细胞的浸润水平以及免疫检查点基因PD-1的表达显著负相关，提示U2SURP可能作为CM免疫治疗的潜在靶点。实验验证表明，U2SURP mRNA和蛋白在CM细胞中过表达，使用siRNA沉默U2SURP可显著降低CM细胞的存活、增殖和迁移。此外，单细胞功能分析表明，U2SURP基因表达与CM细胞增殖和分化呈正相关。本研究系统地鉴定了参与CM的候选剪接因子，并为U2SURP在CM进展中的作用提供了新的见解。这些发现有助于更深入地了解CM的发病机制，并建立识别剪接相关癌症治疗靶点的新方法。
