Department of Pharmacy, Affiliated Hospital of Inner Mongolia Medical University , Hohhot, Inner Mongolia , People's Republic of China.
College of Traditional Mongolia Medicine, Inner Mongolia Medical University , Hohhot, Inner Mongolia , People's Republic of China.
Am J Physiol Gastrointest Liver Physiol. 2019 Apr 1;316(4):G539-G550. doi: 10.1152/ajpgi.00249.2018. Epub 2019 Feb 8.
Hepatic fibrosis is chronic liver damage with many causes that has a relatively high death rate. The current study showed that long noncoding RNA (lncRNA) growth arrest-specific transcript 5 (GAS5), microRNA-23a (miR-23a), and phosphatase and tensin homolog (PTEN) play important roles in the pathological process of hepatic fibrosis but have a relatively unclear regulatory mechanism. This study aimed to investigate the roles of lncRNA GAS5, miR-23a, and PTEN in the pathological process of hepatic fibrosis and hepatic stellate cell (HSC) activation. We used carbon tetrachloride (CCl) intraperitoneal injections to establish a rat hepatic fibrosis model and exogenous transforming growth factor-β1 to establish an HSC activation model. Quantitative RT-PCR, Western blot, dual-luciferase reporter system, and RNA pull-down assays were used to investigate which microRNAs and lncRNAs participate in the process of hepatic fibrosis and HSC activation. miR-23a expression increased significantly in hepatic fibrosis tissues and activated HSCs. miR-23a interaction with and degradation of PTEN further influenced the downstream signaling pathway phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin/Snail (PI3K/Akt/mTOR/Snail), causing E-cadherin expression levels to decrease and α-smooth muscle actin and collagen I expression levels to increase. lncRNA GAS5 can be used as a sponge platform for miR-23a to decrease miR-23a expression levels competitively. We revealed the role of the lncRNA GAS5/miR-23a/PTEN/PI3K/Akt/mTOR/Snail signaling pathway in hepatic fibrosis, providing molecular targets for the treatment of hepatic fibrosis. NEW & NOTEWORTHY This is the first study revealing that microRNA-23a (miR-23a) promotes hepatic fibrosis through the phosphatase and tensin homolog/phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin/Snail signaling pathway, and long noncoding RNA (lncRNA) growth arrest-specific transcript 5 (GAS5) can act as a sponge platform for miR-23a. Therefore, lncRNA GAS5/miR-23a may bring molecular targets for hepatic fibrosis therapy.
肝纤维化是一种由多种原因引起的慢性肝损伤，其死亡率相对较高。本研究表明，长链非编码 RNA（lncRNA）生长停滞特异性转录物 5（GAS5）、微小 RNA-23a（miR-23a）和磷酸酶和张力蛋白同源物（PTEN）在肝纤维化的病理过程中发挥重要作用，但调控机制尚不清楚。本研究旨在探讨 lncRNA GAS5、miR-23a 和 PTEN 在肝纤维化和肝星状细胞（HSC）激活的病理过程中的作用。我们使用四氯化碳（CCl）腹腔注射建立大鼠肝纤维化模型，并用外源性转化生长因子-β1 建立 HSC 激活模型。采用定量 RT-PCR、Western blot、双荧光素酶报告系统和 RNA 下拉实验来研究哪些 microRNAs 和 lncRNAs参与肝纤维化和 HSC 激活过程。miR-23a 在肝纤维化组织和激活的 HSCs 中的表达明显增加。miR-23a 与 PTEN 的相互作用及其降解进一步影响下游信号通路磷脂酰肌醇 3-激酶/蛋白激酶 B/哺乳动物雷帕霉素靶蛋白/Snail（PI3K/Akt/mTOR/Snail），导致 E-钙黏蛋白表达水平降低，α-平滑肌肌动蛋白和胶原 I 表达水平升高。lncRNA GAS5 可以作为 miR-23a 的海绵平台，竞争性降低 miR-23a 的表达水平。我们揭示了 lncRNA GAS5/miR-23a/PTEN/PI3K/Akt/mTOR/Snail 信号通路在肝纤维化中的作用，为肝纤维化的治疗提供了分子靶标。
