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

Abstract

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.

Serum miRNA as a possible biomarker in the diagnosis of bipolar II disorder

“…Briefly, 350-µL serum samples were prepared following the manufacturer's protocol and using the NEBNext small RNA library prep kit (Cat#E7300, New England Biolabs, Ipswich, MA, USA). The detailed process for preparing serum samples was described in our previous study 29 . Afterwards, with the Illumina MiSeq platform, the small RNA libraries were sequenced (150 cycle, single read; MiSeq Reagent kit V3_150 cycles; Illumina, San Diego, CA, USA).…”

Metformin Inhibits Tumor Metastasis through Suppressing Hsp90α Secretion in an AMPKα1-PKCγ Dependent Manner

“…Inhibition of the mTOR/S6/4EBP1 axis is known to impair protein synthesis and cell proliferation [53]. Metformin is also shown to exert regulative functions on miRNAs [6], which results in growth inhibition and cell viability impairment. In addition, metformin has been reported to inhibit epithelial-to-mesenchymal transition (EMT) to suppress tumor progression [10].…”

“…It has been shown that the concentration of metformin had an important effect on its action [43]. The concentration used in this study was based on the previous research [6].…”

“…Some exciting reports show that metformin inhibits tumor progression alone or in combination with other drugs [2][3][4][5]. Varied mechanisms underlying the anti-tumor effect of metformin have been demonstrated in a number of studies [6][7][8][9][10][11][12][13][14]. Metformin can cause demethylation of DNA and lead to up-regulation of some encoding genes and non-coding RNAs, such as miR-192-5p, miR-584-3p, miR-1246, EGF containing fibulin-like extracellular matrix protein 1 (EFEMP1) gene and secretory carrier membrane proteins (SCAMP3) gene [6].…”

“…Varied mechanisms underlying the anti-tumor effect of metformin have been demonstrated in a number of studies [6][7][8][9][10][11][12][13][14]. Metformin can cause demethylation of DNA and lead to up-regulation of some encoding genes and non-coding RNAs, such as miR-192-5p, miR-584-3p, miR-1246, EGF containing fibulin-like extracellular matrix protein 1 (EFEMP1) gene and secretory carrier membrane proteins (SCAMP3) gene [6]. Many studies report that metformin can suppress the growth of tumor by leading to apoptosis and autophagy [7][8][9].…”