Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
Department of Gastroenterology, Affiliated Taizhou Hospital of Wenzhou Medical University, Taizhou, China.
J Cell Biochem. 2019 Mar;120(3):4573-4581. doi: 10.1002/jcb.27746. Epub 2018 Oct 28.
There has been an increasing number of studies about microRNAs as key regulators in the development of hepatic fibrosis. Here, we demonstrate that miR-542-3p can promote hepatic fibrosis by downregulating the expression of bone morphogenetic protein 7 (BMP-7), which is known to antagonize transforming growth factor β1 (TGFβ1)-mediated fibrogenesis effect. The expression of miR-542-3p is increased in activated hepatic stellate cells (HSCs). Downregulation of MiR-542-3p by antisense inhibitors can inhibit HSCs activation markers, including α-smooth muscle actin (α-SMA) and collagen as well as TGFβ signaling pathways. MiR-542-3p was significantly upregulated in carbon tetrachloride (CCl )-induced hepatic fibrosis in mice, and downregulation of miR-542-3p by lentivirus could prevent the development of hepatic fibrosis. In addition, miR-542-3p can directly bind to the 3'-untranslated region of BMP-7 mRNA, indicating that its profibrotic effect appears to be caused by its inhibition of BMP-7. Our results suggest that downregulation of miR-542-3p prevents liver fibrosis both in vitro and in vivo, highlighting its potential as a novel biomarker or therapeutic target for hepatic fibrosis.
越来越多的研究表明 microRNAs 是肝纤维化发展的关键调节因子。在这里，我们证明 miR-542-3p 可以通过下调骨形态发生蛋白 7（BMP-7）的表达来促进肝纤维化，BMP-7 已知拮抗转化生长因子 β1（TGFβ1）介导的纤维生成作用。miR-542-3p 在活化的肝星状细胞（HSCs）中的表达增加。反义抑制剂下调 miR-542-3p 可以抑制 HSCs 激活标志物，包括α-平滑肌肌动蛋白（α-SMA）和胶原以及 TGFβ 信号通路。miR-542-3p 在小鼠四氯化碳（CCl）诱导的肝纤维化中显著上调，通过慢病毒下调 miR-542-3p 可以预防肝纤维化的发展。此外，miR-542-3p 可以直接结合 BMP-7 mRNA 的 3'-非翻译区，表明其促纤维化作用似乎是由其对 BMP-7 的抑制引起的。我们的研究结果表明，下调 miR-542-3p 可预防体外和体内肝纤维化，突出了其作为肝纤维化新的生物标志物或治疗靶标的潜力。
