Gene Expression Changes of Cytokine and Chemokine Receptors Associated with Skin Metastasis in Melanoma

Background: Melanoma is an invasive and highly lethal tumor of the melanocytes and is the leading cause of cutaneous metastases.Dermal endothelial cells have unique properties in metabolism, cytokine signaling, chemotaxis, and cell adhesion.Methods: Our study utilized Matrigel invasion assays to investigate the effect of dermal endothelial cells on melanoma cell invasion and cytokine receptor expression and validated results on tumor and plasma samples from melanoma patients.Real-time quantitative PCR, Proteome Profiler Assay, and Enzyme-Linked Immunosorbent Assay (ELISA) were conducted to investigate the expression of cytokines, chemokines, and their receptors.Results: Co-culturing melanoma and endothelial cells revealed distinct expression of several cytokine receptor genes (CCR5, CXCR7, IL1RAPL2, IL4R, IL6ST, IL18R1, IL22RA2, TNFRSF10A, TNFRSF11B, and TNFRSF21) and cytokine ligands (Midkine, GRO, MIP-3, IL-8, and SDF-1) in relation to dermal invasion.We found that the expression of the IL1RAPL2 gene was significantly higher in primary melanomas with distant metastasis compared to primary melanoma tumors with skin metastasis and metastatic melanomas of the skin.The expression of the TNFRSF10A gene was significantly lower in dermal melanoma metastases compared to primary melanomas with distant metastasis.We detected higher plasma levels of Midkine in patients with skin metastasis than those with distant or without metastasis.Plasma concentrations of MIP-3 were significantly lower in patients with metastatic tumors than those with primary melanoma.Additionally, GRO exhibited significantly higher plasma levels in patients with thinner tumors than thicker tumors, and a significant positive correlation was observed between IL6ST gene expression and melanoma tumor thickness.Conclusions: In conclusion, our data suggest that a higher plasma level of Midkine may be associated with the formation of skin metastasis.Additionally, we propose a possible association between the downregulation of the IL1RAPL2 and TNFRSF10A genes and the development of melanoma skin metastasis.