Zheng Jianjian, Dong Peihong, Mao Yuqing, Chen Shaolong, Wu Xiaoli, Li Guojun, Lu Zhongqiu, Yu Fujun
Wenzhou Key Laboratory of Surgery, The First Affiliated Hospital of Wenzhou Medical University, China.
Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, China.
FEBS J. 2015 Dec;282(24):4810-21. doi: 10.1111/febs.13544. Epub 2015 Oct 26.
Long non-coding RNAs are involved in various biological processes and diseases. The biological role of long intergenic non-coding RNA-p21 (lincRNA-p21) in liver fibrosis remains unknown before this study. In this study, we observed marked reduction of lincRNA-p21 expression in mice liver fibrosis models and human cirrhotic liver. Over-expression of lincRNA-p21 suppressed activation of hepatic stellate cells (HSCs) in vitro. Lentivirus-mediated lincRNA-p21 transfer into mice decreased the severity of liver fibrosis in vivo. Additionally, lincRNA-p21 reversed the activation of HSCs to their quiescent phenotype. The mRNA levels of lincRNA-p21 and p21 were positively correlated. Our results show that over-expression of lincRNA-p21 promotes up-regulation of p21 at both the mRNA and protein levels. Furthermore, lincRNA-p21 inhibited cell-cycle progression and proliferation of primary HSCs through enhancement of p21 expression. Compared with healthy subjects, serum lincRNA-p21 levels were significantly lower in patients with liver cirrhosis, especially those with decompensation. These findings collectively indicate that lincRNA-p21 is a mediator of HSC activation, supporting its utility as a novel therapeutic target for liver fibrosis.
长链非编码RNA参与多种生物学过程和疾病。在本研究之前，长链基因间非编码RNA-p21（lincRNA-p21）在肝纤维化中的生物学作用尚不清楚。在本研究中，我们观察到在小鼠肝纤维化模型和人类肝硬化肝脏中lincRNA-p21表达显著降低。lincRNA-p21的过表达在体外抑制肝星状细胞（HSC）的激活。慢病毒介导的lincRNA-p21转入小鼠体内可降低体内肝纤维化的严重程度。此外，lincRNA-p21使HSC的激活逆转至其静止表型。lincRNA-p21和p21的mRNA水平呈正相关。我们的结果表明，lincRNA-p21的过表达在mRNA和蛋白质水平上均促进p21的上调。此外，lincRNA-p21通过增强p21的表达抑制原代HSC的细胞周期进程和增殖。与健康受试者相比，肝硬化患者血清lincRNA-p21水平显著降低，尤其是失代偿期患者。这些发现共同表明，lincRNA-p21是HSC激活的介质，支持其作为肝纤维化新治疗靶点的实用性。
