In Silico Analysis of Novel circRNA-miRNA-mRNA Axis in BRAFV600E Melanoma: Implications for Primary to Metastasis Transformation and TIME Modulation.

The BRAFV600E mutation drives metastatic transition by altering the tumor immune microenvironment (TIME) through transcriptional and post-transcriptional regulation. Recent studies identify circular RNA (circRNA) and micro-RNA (miRNA) as key regulators in melanoma. This study uses in silico analysis to explore the circRNA-miRNA-mRNA axis in melanoma progression. We analyzed primary (n = 42) and metastatic (n = 89) tumor samples from TCGA (SKCM), including their BRAF status, to identify markers in both tumor types and explored their association with immune cells within TIME. The key regulatory markers were verified using ROC curve analysis, IHC data from HPA database, and from an external dataset. Further, the circRNA-miRNA-mRNA axis was established using Cytoscape. Our comprehensive analysis identifies SYK, HMOX1, IL33, CFH, FGF1, COL8A1, and ADAMTS3 as the primary gene signatures, while VCAM-1 and SNAI2 dominate as prominent metastatic markers associated with BRAFV600E and immune subtype. Among the immune infiltrating group, macrophages M1 and M2, CD8+ T-cells, and Tregs show a positive correlation with significant infiltration within TIME. We screened miRNA targets and circular sponges, built a circRNA-miRNA-mRNA network involving two circRNAs (hsa-circ-0011617 and hsa-circ-0011623) and three miRNAs (hsa-miR-1246, hsa-miR-346, and hsa-miR-1197) connected to the identified signature. Overall, our study reveals two circRNAs that might have a potential role in primary to metastasis transition in the BRAF-mutated melanoma within TIME via the circRNA-miRNA-mRNA axis.