Abstract Melanoma is the most lethal form of skin cancer, characterized by an increasing incidence and high mortality rates globally. However, the mechanisms underlying melanoma tumorigenesis and progression remain poorly understood. Analyses of public repositories have identified SERPINE2 as a key differentially expressed gene involved in the biological processes associated with melanoma. As a member of the serpin superfamily, SERPINE2 plays diverse roles in regulating proteolytic activity, inflammation, and tissue remodeling; however, its specific functions in melanoma warrant further investigation. This study aims to explore the potential mechanisms by which SERPINE2 influences tumorigenesis and progression in melanoma. In this study, we evaluated the expression and clinical relevance of SERPINE2 in melanoma by analyzing data from TCGA, GTEx, and TIMER2.0, and identified SERPINE2-associated biological processes through GO and KEGG enrichment analyses. Our findings revealed that SERPINE2 is significantly upregulated in melanoma tissues compared to normal skin tissues, and its expression correlates with cell growth, epithelial-mesenchymal transition, and immune response. Knockdown of SERPINE2 markedly inhibited cell viability, proliferation, and invasion of melanoma cells both in vitro and in vivo. RNA sequencing analysis of SERPINE2-knockdown cell lines demonstrated that silencing SERPINE2 induced cell cycle arrest in the G0/G1 phase and promoted apoptosis. To investigate the underlying mechanisms, we identified DDX3X as a binding partner of SERPINE2 through co-immunoprecipitation (CO-IP) and immunoprecipitation-mass spectrometry (IP-MS) analyses. We found that SERPINE2 attenuates the protein stability of DDX3X, promoting its degradation via the ubiquitin-proteasome system. Furthermore, silencing DDX3X resulted in the downregulation of nuclear protein expression of MITF and p21, suggesting that DDX3X downregulation may influence the transcription of downstream genes associated with cell cycle progression, thereby impacting melanoma growth. Additionally, downregulation of SERPINE2 enhanced CD8+ T cell infiltration, stimulated T-cell activation-related cytokines and chemokines, and improved the cytotoxic function of CD8+ T cells in vitro. Furthermore, in both the Lauss cohort and the IMvigor210 cohort, we observed that SERPINE2 expression correlated with the prognosis of melanoma patients undergoing immunotherapy; specifically, patients with low SERPINE2 expression exhibited better prognoses compared to those with high SERPINE2 expression. In summary, the expression level of SERPINE2 is a predictor of therapy response and prognosis in melanoma patients, suggesting its potential as a biomarker for melanoma immunotherapy. This work was supported by the National Natural Science Foundation of China (No. 82173336), and the MRI Project (G030410001). Citation Format: Qirui Liu, Xin Huang, Xiao Zhang, Xinyu Ye, Yi Lu, Jian Zhang. Serpine2 promotes melanoma progression through the modulation of the DDX3X/MITF/p21 signaling pathway abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1915.
Liu et al. (Fri,) studied this question.