Integrated transcriptomic profiling identifies a core gene signature associated with melanoma progression and radiotherapy-related immune suppression

Using a combined computational and experimental framework, this work sought to systematically pinpoint key genes that link melanoma progression with transcriptional alterations associated with radiotherapy. Differential expression analyses were performed in TCGA-SKCM comparing radiotherapy (RT, n = 120) versus non-radiotherapy (NoRT, n = 23) samples and in an independent paired dataset (44 tumor/adjacent normal pairs). GO/KEGG and Hallmark GSEA were conducted, followed by intersection analysis to define shared candidates. Candidate genes were validated in HEMa-LP, A375, and SK-MEL-2 using qRT-PCR and Western blotting. Radiosensitivity was further assessed by gene knockdown followed by 4 Gy irradiation and CCK-8 assay. RT versus NoRT analysis identified 1485 DEGs (1051 up; 434 down) and revealed a radiotherapy-associated “barrier enhancement–immune suppression” signature, with enrichment of keratinization/epidermal differentiation and suppression of B-cell/lymphocyte-related pathways, primarily reflecting reduced immune-cell–associated transcriptional programs within the tumor microenvironment as inferred from bulk transcriptomic data. Cross-comparison of upregulated genes yielded 10 shared core genes (VGF, HES6, APOC2, RLBP1, CHIT1, MIR3189, IGHV3-20, HS3ST2, KU-MEL-3, COL11A2). Compared with normal melanocytes, melanoma cell lines showed marked mRNA upregulation of all 10 genes, and protein-level overexpression was further verified for eight of them. Furthermore, knockdown of eight selected genes significantly reduced post-irradiation cell viability, indicating enhanced radiosensitivity in melanoma cells. Integrated transcriptomic analyses and in vitro validation identified a 10-gene core signature jointly linked to melanoma progression and radiotherapy-associated profiles, providing prioritized candidates for mechanistic studies of melanoma radioresistance.