ASIC1a regulates miR-350/SPRY2 by N 6 -methyladenosine to promote liver fibrosis.
FASEB JOURNAL(2020)
Abstract
As a reversible scar repair reaction, liver fibrosis can be blocked or even reversed by proper intervention during its formation. Our work suggests that acid-sensitive ion channel 1a (ASIC1a) participates in liver fibrosis and presents a novel mechanism involving m(6)A modification and miR-350/SPRY2. We demonstrated that the expression of ASIC1a was significantly increased in liver tissue of patients with liver fibrosis and animal models of liver fibrosis, as well as PDGF-BB-induced activated HSC-T6. After downregulating the expression of ASIC1a, the degree of liver fibrosis is reduced and HSC activation was inhibited, the level of m(6)A modification and miR-350 expression were also reduced. The results of dual luciferase reporter assay showed that miR-350 can bind to the target gene SPRY2 and inhibit its expression. We also found that METTL3 can regulate the extent of m(6)A modification of pri-miR-350 by binding to DGCR8. In addition, silencing or blocking the expression of ASIC1a can reduce the expression of PI3K/AKT and ERK signaling pathway-related proteins in activated HSCs. Taken together, we demonstrated that ASIC1a regulates the processing of miR-350 through METTL3-dependent m(6)A modification, and mature miR-350 targets SPRY2 and further promotes liver fibrosis through the PI3K/KT and ERK pathways.
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Key words
ASIC1a,HSC,SPRY2,METTL3,miR-350
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