miR-3606-3p alleviates skin fibrosis by suppressing fibroblast inflammation and migration via inhibiting GAB1 and ITGAV

Abstract

Abstract Systemic sclerosis (SSc) and keloid are typical skin fibrotic diseases with unclear epigenetic mechanisms and clinical targets, this study aimed to assess the role of miR-3606-3p in skin fibrosis and the therapeutic potential. MiR-3606-3p was reduced in the skin tissues and fibroblasts from both SSc and keloid patients. RNA-seq analysis and in silico prediction indicated GRB2 associated binding protein 1 (GAB1) and integrin subunit alpha V (ITGAV) were potential targets of miR-3606-3p. We then found that miR-3606-3p downregulated both GAB1 and ITGAV by directly targeting their 3′-UTRs, and further reduced p-AKT and p-ERK activities to inhibit collagen synthesis and fibroblast inflammation. Furthermore, miR-3606-3p inhibited fibroblast migration in primary fibroblasts and keloid-bearing nude mice by wound healing scratch assay and in vivo imaging techniques respectively. In contrast, GAB1 and ITGAV were upregulated in SSc and keloid patients, and siRNA-mediated GAB1 or ITGAV knockdown replicated the phenotypes observed in miR-3606-3p-overexpressing fibroblasts, including inflammation, migration and fibrogenesis. Finally, in vivo experiments showed that miR-3606-3p treatment significantly alleviates skin fibrosis in keloid-bearing mice. Our results indicated miR-3606-3p inhibits ECM deposition, inflammation, and migration of fibroblasts by downregulating GAB1 and ITGAV. miR-3606-3p-enhancing strategies may have beneficial effects on skin fibrosis through lowing p-AKT/p-ERK activity.