ASIC1a regulates miR‐350/SPRY2 by N ⁶ ‐methyladenosine to promote liver fibrosis

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.

Comprehensive Analysis of the Transcriptome-Wide m6A Methylation Modification Difference in Liver Fibrosis Mice by High-Throughput m6A Sequencing

“…With regard to the effect of m6A methylation on the biological function of liver cells, existing studies have focused on the regulatory mechanism of genes and pathways ( Zhang C. et al, 2020 ; Cao et al, 2021 ). A study by Zhu Y. et al (2020) found that METTL3-mediated m6A methylation could be regulated by ASIC1a, which in turn affects the processing of miR-350, thus inducing the activation of HSCs and promoting the occurrence and development of LF. Unlike their studies, our study compared the difference in m6A methylation between the control and LF liver tissue, and confirmed that the m6A modification level changed significantly in LF.…”

Signaling Pathways in Proton and Non-proton ASIC1a Activation

“…(an approximately half-fold) the levels of CaMKKß and ERK phosphorylation in a cell line of hepatic fibroblasts stimulated by high glucose and PDGF (Wang et al, 2019). Zhu et al (2020) showed a contribution of ASIC1a to increased ERK phosphorylation in the mechanism of liver fibrosis, as Pctx-1 treatment decreased the approximate 2-fold increase (without treatment) to a 1.5-fold increase. The same can be observed in ERK phosphorylated levels as the bands show a greater intensity for ERK-mediated NF-κB activation through ASIC1 in response to acidosis (although not quantified; Chen et al, 2016).…”

“…As an example, the activation of ERK via ASIC1a (downstream ASIC1a activation) has been analyzed in different pathological conditions (Chen et al, 2016;Sun et al, 2018;Zhu et al, 2020Zhu et al, , 2021. In addition, this pathway has also been linked to inflammation (Yu et al, 2015).…”

Pathology and physiology of acid‑sensitive ion channels in the digestive system (Review)

“…ASIC1a is expressed in rat hepatic stellate cells, suggesting that the formation of liver fibrosis is related to ASIC1a ( 112 ). Zhu et al ( 113 ) found that ASIC1a expression was significantly increased in liver fibrosis, and miR-350 was involved in the formation of liver fibrosis regulated by ASIC1a and activation of stellate cells. Further analysis proved that the mechanism of hepatic fibrosis caused by ASIC1a was via ASIC1a-mediated regulation of m6A to affect the processing and modification of miR-350, and participate in hepatic fibrosis through modulation of the PI3K/AKT and ERK pathways ( Fig.…”