综合系统生物学分析揭示剪接因子对皮肤黑色素瘤进展的贡献

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.