Department of Infectious Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, China.
Hum Cell. 2024 Mar;37(2):435-450. doi: 10.1007/s13577-023-01017-y. Epub 2024 Jan 14.
Continuously progressive hepatic fibrosis might cause chronic liver diseases, resulting in hepatic failure. The activation of hepatic stellate cells (HSCs) residing in the liver might induce and influence hepatic fibrosis. In the present study, microRNA 3074 (miR-3074) was found increased within transforming growth factor-β (TGF-β)-activated HSCs and enriched within the TGF-β signaling. In activated HSCs by TGF-β, miR-3074 overexpression aggravated TGF-β-induced fibrotic changes, whereas miR-3074 inhibition exerted opposite effects. miR-3074 directly targeted bone morphogenetic protein 7 (BMP7) and inhibited BMP7 expression. Under TGF-β induction, overexpressed BMP7 notably attenuated the promotive roles of miR-3074 overexpression in TGF-β-activated HSCs. Within carbon tetrachloride (CCl)-caused liver fibrosis murine model, miR-3074 agomir administration promoted, while LV-BMP7 administration alleviated CCl-induced fibrotic changes; LV-BMP7 significantly attenuated the effects of miR-3074 agomir. Lastly, mmu-miR-3074 also targeted mouse BMP7 and inhibited mouse BMP7 expression. In conclusion, the miR-3074/BMP7 axis regulates TGF-β-caused activation of HSCs in vitro and CCl-caused murine liver fibrosis in vivo. BMP7-mediated Smad1/5/8 activation might be involved.
持续进展的肝纤维化可能导致慢性肝病，从而导致肝衰竭。肝星状细胞（HSCs）的激活可能诱导和影响肝纤维化。在本研究中，发现 microRNA 3074（miR-3074）在转化生长因子-β（TGF-β）激活的 HSCs 中增加，并在 TGF-β 信号中富集。在 TGF-β激活的 HSCs 中，miR-3074 的过表达加重了 TGF-β诱导的纤维化变化，而 miR-3074 的抑制则产生了相反的效果。miR-3074 直接靶向骨形态发生蛋白 7（BMP7）并抑制 BMP7 的表达。在 TGF-β诱导下，过表达的 BMP7 显著减弱了 miR-3074 过表达在 TGF-β 激活的 HSCs 中的促进作用。在四氯化碳（CCl）引起的肝纤维化小鼠模型中，miR-3074 激动剂的给药促进了，而 LV-BMP7 的给药减轻了 CCl 引起的纤维化变化；LV-BMP7 显著减弱了 miR-3074 激动剂的作用。最后，mmu-miR-3074 还靶向小鼠 BMP7 并抑制小鼠 BMP7 的表达。总之，miR-3074/BMP7 轴调节体外 TGF-β 引起的 HSCs 激活和体内 CCl 引起的小鼠肝纤维化。可能涉及 BMP7 介导的 Smad1/5/8 激活。
