Metformin Treatment Suppresses Melanoma Cell Growth and Motility through Modulation of microRNA Expression

Melanoma is a highly aggressive cancer with high mortality in advanced stages. Metformin is an oral biguanide drug used for diabetes and has demonstrated positive effects on cancer prevention and treatment. Herein, we found that metformin significantly suppressed melanoma cancer cell motility and growth through inducing cell cycle arrest at the G2/M phase and promoting cell apoptosis. Using the next-generation sequencing approach, we identified three upregulated microRNAs (miRNA; miR-192-5p, miR-584-3p, and miR-1246) in melanoma cells treated with metformin. Among these, we examined the roles of miR-192-5p and miR-584-3p and discovered that they significantly suppressed melanoma cell motility. Furthermore, they inhibited melanoma cell growth through destroying cell cycle progression and inducing cell apoptosis. Using microarray and bioinformatics approaches for identifying putative target genes, Epidermal growth factor (EGF) containing fibulin-like extracellular matrix protein 1 (EFEMP1) gene for miR-192-5p and an isoform of the secretory carrier membrane proteins (SCAMP3) gene for miR-584-3p could be silenced through targeting their 3′UTR region directly. EFEMP1 and SCAMP3 knockdown significantly suppressed melanoma cell growth, but only EFEMP1 knockdown inhibited its motility abilities. Our findings indicated that miR-192-5p and miR-584-3p might contribute to metformin-induced growth and motility suppression in melanoma cells through silencing their target genes EFEMP1 and SCAMP3.