ASIC1a regulates miR-350/SPRY2 by N6 -methyladenosine to promote liver fibrosis.

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 m6 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 m6 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 m6 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 m6 A modification, and mature miR-350 targets SPRY2 and further promotes liver fibrosis through the PI3K/KT and ERK pathways. © 2020 Federation of American Societies for Experimental Biology.

Citation

Yueqin Zhu, Xuesheng Pan, Na Du, Kuayue Li, Yamin Hu, Lili Wang, Jin Zhang, Yanyi Liu, Longquan Zuo, Xiaoming Meng, Chengmu Hu, Xian Wu, Juan Jin, Wenyong Wu, Xiangtao Chen, Fanrong Wu, Yan Huang. ASIC1a regulates miR-350/SPRY2 by N6 -methyladenosine to promote liver fibrosis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2020 Nov;34(11):14371-14388

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PMID: 32949431

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