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 oncancer prevention and treatment. Herein, we found that metformin significantly suppressedmelanoma cancer cell motility and growth through inducing cell cycle arrest at the G2/M phase andpromoting cell apoptosis. Using the next-generation sequencing approach, we identified threeupregulated microRNAs (miRNA; miR-192-5p, miR-584-3p, and miR-1246) in melanoma cellstreated with metformin. Among these, we examined the roles of miR-192-5p and miR-584-3p anddiscovered that they significantly suppressed melanoma cell motility. Furthermore, they inhibitedmelanoma cell growth through destroying cell cycle progression and inducing cell apoptosis. Usingmicroarray and bioinformatics approaches for identifying putative target genes, Epidermal growthfactor (EGF) containing fibulin-like extracellular matrix protein 1 (EFEMP1) gene for miR-192-5pand an isoform of the secretory carrier membrane proteins (SCAMP3) gene for miR-584-3p could besilenced through targeting their 3'UTR region directly. EFEMP1 and SCAMP3 knockdownsignificantly suppressed melanoma cell growth, but only EFEMP1 knockdown inhibited its motilityabilities. Our findings indicated that miR-192-5p and miR-584-3p might contribute to metformininducedgrowth and motility suppression in melanoma cells through silencing their target genesEFEMP1 and SCAMP3.