miR-374b-5p Modulates Melanoma Progression by Targeting VEGFC and Regulating MAPK Signaling in the Tumor...

Melanoma is an aggressive skin cancer with high metastatic potential and poor long-term survival, highlighting the need for new therapeutic targets. Although microRNAs are critical regulators of tumor progression, the function of miR-374b-5p in melanoma remains poorly understood. Here, we identify miR-374b-5p as a tumor suppressor in melanoma cells. We show that miR-374b-5p directly targets vascular endothelial growth factor C (Vegfc) and is associated with changes in mitogen-activated protein kinase (MAPK) signaling, accompanied by reduced levels of phosphorylated extracellular signal-regulated kinase (pERK) and tyrosinase (TYR). Consistent with these observations, miR-374b-5p overexpression suppresses melanoma cell proliferation, migration, and invasion in vitro. Conditioned media from miR-374b-5p-overexpressing melanoma cells is also associated with changes in macrophage-related inflammatory markers, suggesting that these alterations are consistent with a shift toward a more pro-inflammatory macrophage phenotype. In a mouse model, miR-374b-5p overexpression significantly reduced tumor growth and angiogenesis, and downregulated the lymphangiogenic factor VEGFC. Together, these findings identify miR-374b-5p as a novel regulator of melanoma progression that acts through VEGFC-associated MAPK signaling and tumor microenvironment reprogramming, identifying miR-374b-5p as a promising therapeutic candidate for melanoma.