m6A RNA methylation regulator-associated genes drive metastasis and immune cell infiltration in skin cutaneous melanoma.

Skin cutaneous melanoma (SKCM) is a highly aggressive malignancy, and understanding the mechanisms underlying its metastasis is essential for improving patient prognosis. N6-methyladenosine (m6A) RNA modification is involved in tumor progression; however, its specific role in SKCM metastasis remains poorly defined. The present study aimed to identify m6A-related regulatory genes associated with SKCM metastasis and to assess their impact on the tumor immune microenvironment. Expression data from primary and metastatic SKCM samples were obtained from the Gene Expression Omnibus (GSE8401, GSE15605, GSE46517 and GSE65904) and The Cancer Genome Atlas-SKCM databases. A metastasis-risk prediction model was constructed using least absolute shrinkage and selection operator-Cox regression analysis. Differential expression analysis, functional enrichment, Pearson correlation, single-sample gene set enrichment analysis and competing endogenous (ce)RNA network analysis were performed. Key gene expression levels were evaluated using reverse transcription-quantitative PCR and immunohistochemistry. A total of 94 metastasis-related mRNAs were identified as differentially expressed, of which 45 demonstrated significant associations with m6A regulators. Among them, 12 genes were associated with patient prognosis, with cadherin 3 (CDH3), keratin 17 (KRT17), plakophilin 1 (PKP1) and cellular retinoic acid binding protein 2 (CRABP2) identified as key candidates. A ceRNA network comprising these four mRNAs, 13 long noncoding RNAs, and 20 microRNAs was constructed. These core genes demonstrated significantly higher expression levels in tumor tissues compared with in adjacent normal tissues, were associated with a worse overall survival, and revealed strong correlations with immune cell infiltration, particularly mast cells and Th17 cells. In conclusion, m6A RNA modification may contribute to SKCM metastasis by regulating the expression of CDH3, KRT17, PKP1 and CRABP2, as well as modulating the tumor immune microenvironment. These findings offer novel insights into the metastatic mechanisms of SKCM and identify potential biomarkers for its diagnosis, prognosis and targeted immunotherapy.