Dasatinib ameliorates thioacetamide-induced liver fibrosis: modulation of miR-378 and miR-17 and their linked Wnt/b-catenin and TGF-b/smads pathways

Abstract

Hepatic stellate cells activation (HSCs) plays a crucial role in the pathogenesis of liver fibrosis. Specific microRNAs have been suggested to affect the activation of HSCs via various signalling pathways including TGF-b/smads and Wnt/b-catenin pathways. Dasatinib is a multitarget inhibitor of many tyrosine kinases has recently studied for its anti-fibrotic effects in a variety of fibrous diseases. This study investigated the role of modulation of miRNA-378 and miRNA-17 in the pathogenesis of liver fibrosis through altering Wnt/b-catenin and TGF-b/smads pathways and evaluated the beneficial effect of the tyrosine kinase inhibi- tor, dasatinib, in thioacetamide-induced liver fibrosis model in mice. Treatment with dasatinib down-regu- lated miRNA-17 expression, leading to the restoration of WiF-1 and smad-7 which cause the inhibition of both Wnt/b-catenin and TGF-b/smads signalling. In addition, it upregulated miRNA-378 leading to the decrease of Wnt-10 which contributes to the suppression of activated HSCs.