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

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 <i>miR-374b-5p</i> in melanoma remains poorly understood. Here, we identify <i>miR-374b-5p</i> as a tumor suppressor in melanoma cells. We show that <i>miR-374b-5p</i> directly targets <i>vascular endothelial growth factor C</i> (<i>Vegfc</i>) 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, <i>miR-374b-5p</i> overexpression suppresses melanoma cell proliferation, migration, and invasion in vitro. Conditioned media from <i>miR-374b-5p</i>-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, <i>miR-374b-5p</i> overexpression significantly reduced tumor growth and angiogenesis, and downregulated the lymphangiogenic factor VEGFC. Together, these findings identify <i>miR-374b-5p</i> as a novel regulator of melanoma progression that acts through VEGFC-associated MAPK signaling and tumor microenvironment reprogramming, identifying <i>miR-374b-5p</i> as a promising therapeutic candidate for melanoma.