Department of Hepatopathy, The Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha 410005, China.
Department of Hepatopathy, The Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha 410005, China.
Toxicol Lett. 2022 Jun 1;362:38-49. doi: 10.1016/j.toxlet.2022.04.004. Epub 2022 Apr 26.
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 CCl-caused liver fibrosis murine model, Anxa6 knockdown partially ameliorated CCl-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 CCl-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.
慢性肝脏疾病，如肝纤维化，是发病率和死亡率的主要原因，并且与肝细胞癌（HCC）的个体高风险相关。肝星状细胞（HSCs）的激活是肝纤维化进展的核心事件。在本研究中，发现在肝纤维化中长链非编码 RNA ANXA2P2（小鼠 Anxa6）上调。在 CCl 引起的肝纤维化小鼠模型中，Anxa6 敲低部分改善了 CCl 引起的肝纤维化，并阻断了 PI3K/Akt 信号激活。在 TGF-β1 刺激的 HSCs 中，Anxa6 敲低部分抑制了 TGF-β1 诱导的 HSC 激活，并阻断了 PI3K/Akt 信号激活。小鼠 Anxa6 的下游 mmu-miR-9-5p 直接靶向 Anxa2；Anxa6 负调控 mmu-miR-9-5p，而 mmu-miR-9-5p 负调控小鼠 Anxa2。在 TGF-β1 刺激的 HSCs 中，miR-9-5p 抑制剂促进了 TGF-β1 诱导的 HSC 激活和 PI3K/Akt 信号激活，而 Anxa2 敲低则产生相反的效果；Anxa2 敲低显著减弱了 miR-9-5p 抑制剂对 TGF-β1 刺激的 HSCs 的作用。总之，长链非编码 RNA ANXA2P2（小鼠 Anxa6）在肝纤维化中表达上调，并对 CCl 引起的肝纤维化模型小鼠和 TGF-β1 刺激的 HSCs 发挥促纤维化作用。小鼠 Anxa6/miR-9-5p/Anxa2 轴和 PI3K/Akt 途径可能参与了长链非编码 RNA ANXA2P2（小鼠 Anxa6）在肝纤维化中的功能。
