MUCL1 functions as a tumor suppressor in skin melanoma by inhibiting epithelial–mesenchymal transition

This study aims to analyze the global burden of skin melanoma from 1990 to 2021 and explore the clinical significance and mechanistic role of Mucin-Like Protein 1 (MUCL1) in the metastasis of skin melanoma. Global burden data from 1990 to 2021 were extracted from the Global Burden of Disease (GBD) 2021 database to provide epidemiological background. To validate the clinical relevance of MUCL1, we examined MUCL1 expression and its associations with clinicopathological parameters (AJCC stage, T classification, metastatic status) and EMT markers (CDH1, CDH2) in the publicly available TCGA-SKCM cohort ( n = 473), complemented by ssGSEA for pathway analysis; additionally, we collected 30 skin melanoma tissues and 30 matched adjacent non-tumor tissues and analyzed MUCL1 and N-cadherin expression by immunohistochemistry (IHC). For in vitro mechanistic studies, MUCL1 expression in HaCaT, A375, A2058, and SK-MEL-1 cells was assessed by qPCR and western blot (WB); A375 and A2058 cells were transfected with si-MUCL1 and ov-MUCL1, respectively. EMT-related proteins were quantified by immunofluorescence double staining and WB, and cell proliferation, migration, and invasion were evaluated by CCK-8, scratch wound healing, and Transwell assays. GBD analysis showed that the burden of skin melanoma in 2021 was highest in Australia and New Zealand, concentrated in the 50–74-year age group, and higher in males and high-SDI regions. In the TCGA-SKCM cohort and IHC samples, MUCL1 was significantly downregulated in melanoma, and its low expression was associated with metastatic status, advanced AJCC stage, and deeper T classification. MUCL1 was positively correlated with CDH1 and negatively correlated with CDH2; ssGSEA showed negative correlations with cell-cycle pathways (G2M, E2F, MYC) and positive correlations with apoptosis and p53 pathways. In in vitro experiments, overexpression of MUCL1 upregulated E-cadherin, downregulated N-cadherin, Vimentin, Snail, and Slug, and inhibited cell proliferation, migration, and invasion, whereas silencing MUCL1 produced the opposite effects. MUCL1 is downregulated in skin melanoma, and its low expression is associated with disease progression at both the clinical cohort and mechanistic levels. These findings support MUCL1 as a potential tumor suppressor in skin melanoma and lay the foundation for future translational research.