Yu Fujun, Chen Bicheng, Dong Peihong, Zheng Jianjian
Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China; Department of Gastroenterology, Songjiang Hospital Affiliated Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai 201600, China; Department of Gastroenterology, Shanghai Songjiang Hospital Affiliated to Nanjing Medical University, Nanjing 210029, China.
Key Laboratory of Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
Mol Ther. 2017 Jan 4;25(1):205-217. doi: 10.1016/j.ymthe.2016.10.015.
Homeobox transcript antisense RNA (HOTAIR), as a long intergenic non-coding RNA (lincRNA), is upregulated in various cancers and involved in diverse cellular functions. However, its role in liver fibrosis is unclear. In this study, HOTAIR expression was upregulated in hepatic stellate cells (HSCs) in vivo and in vitro during liver fibrosis. HOTAIR knockdown suppressed HSC activation including α-smooth muscle actin (α-SMA) and typeIcollagen in vitro and in vivo. Both HSC proliferation and cell cycle were inhibited by HOTAIR knockdown. Notably, inhibition of HOTAIR led to an increase in PTEN, associated with the loss of DNA methylation. miR-29b-mediated control of PTEN methylation was involved in the effects of HOTAIR knockdown. HOTAIR was confirmed a target of miR-29b and lack of the miR-29b binding site in HOTAIR prevented the suppression of miR-29b, suggesting HOTAIR contributes to PTEN expression downregulation via sponging miR-29b. Interestingly, increased HOTAIR was also observed in hepatocytes during liver fibrosis. Loss of HOTAIR additionally led to the increase in PTEN and the reduction in typeIcollagen in hepatocytes. Collectively, we demonstrate that HOTAIR downregulates miR-29b expression and attenuates its control on epigenetic regulation, leading to enhanced PTEN methylation, which contributes to the progression of liver fibrosis.
同源框转录反义RNA（HOTAIR）作为一种长链基因间非编码RNA（lincRNA），在多种癌症中上调，并参与多种细胞功能。然而，其在肝纤维化中的作用尚不清楚。在本研究中，在肝纤维化过程中，体内和体外肝星状细胞（HSCs）中HOTAIR表达均上调。敲低HOTAIR在体内和体外均抑制HSC激活，包括α平滑肌肌动蛋白（α-SMA）和I型胶原蛋白。敲低HOTAIR可抑制HSC增殖和细胞周期。值得注意的是，抑制HOTAIR导致PTEN增加，这与DNA甲基化缺失有关。miR-29b介导的PTEN甲基化调控参与了敲低HOTAIR的效应。HOTAIR被证实是miR-29b的靶标，且HOTAIR中缺乏miR-29b结合位点可阻止miR-29b的抑制作用，表明HOTAIR通过海绵吸附miR-29b促进PTEN表达下调。有趣的是，在肝纤维化过程中肝细胞中也观察到HOTAIR增加。缺失HOTAIR还导致肝细胞中PTEN增加和I型胶原蛋白减少。总体而言，我们证明HOTAIR下调miR-29b表达并减弱其对表观遗传调控的控制，导致PTEN甲基化增强，这促进了肝纤维化的进展。
