The mouse Anxa6/miR-9-5p/Anxa2 axis modulates TGF-β1-induced mouse hepatic stellate cell (mHSC) activation and CCl4-caused liver fibrosis

• Published in: Toxicology letters Vol. 362; pp. 38 - 49
• Main Authors: Liao, Jinmao, Zhang, Zheng, Yuan, Qi, Luo, Lidan, Hu, Xiaoxuan
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01-06-2022
• Subjects: Anxa2; Hepatic fibrosis; LncRNA ANXA2P2 (mouse Anxa6); miR-9-5p; Mouse hepatic stellate cells (mHSCs); Hepatic fibrosis; Anxa2; LncRNA ANXA2P2 (mouse Anxa6); Mouse hepatic stellate cells (mHSCs); miR-9-5p
• ISSN: 0378-4274; 1879-3169
• DOI: 10.1016/j.toxlet.2022.04.004

Chronic liver disease such as hepatic fibrosis is a major cause of morbidity and mortality and has been related to high individual risk of hepatocellular carcinoma (HCC). Hepatic stellate cells (HSCs) activation is a central event of hepatic fibrosis progression. In this study, the up-regulation of lncRNA ANXA2P2 (mouse Anxa6) was found in liver fibrosis. Within CCl4-caused liver fibrosis murine model, Anxa6 knockdown partially ameliorated CCl4-induced hepatic fibrosis and blocked the PI3K/Akt signaling activation. In TGF-β1-stimulated HSCs, Anxa6 knockdown partially inhibited TGF-β1-induced HSC activation and blocked the PI3K/Akt signaling activation. Mouse Anxa6 downstream mmu-miR-9-5p directly targeted Anxa2; Anxa6 negatively regulated mmu-miR-9-5p, and mmu-miR-9-5p negatively regulated mouse Anxa2. In TGF-β1-stimulated HSCs, miR-9-5p inhibitor promoted TGF-β1-induced HSC activation and PI3K/Akt signaling activation, whereas Anxa2 knockdown exerted opposite effects; Anxa2 knockdown significantly attenuated miR-9-5p inhibitor effects upon TGF-β1-stimulated HSCs. In conclusion, lncRNA ANXA2P2 (mouse Anxa6) expression is up-regulated in hepatic fibrosis and exerts pro-fibrotic effects on CCl4-caused liver fibrosis model mice and TGF-β1-stimulated HSCs. The mouse Anxa6/miR-9-5p/Anxa2 axis and the PI3K/Akt pathway might participate in the functions of lncRNA ANXA2P2 (mouse Anxa6) on hepatic fibrosis.
•LncRNA Anxa6 knockdown improves liver fibrosis in mouse and inhibits HSC activation.•miR-9-5p directly targets lncRNA Anxa6 and Anxa2.•Anxa6/miR-9-5p/Anxa2 axis modulates HSC activation by regulating PI3K/Akt signaling.