Wang Qi, Wei Song, Li Lei, Bu Qingfa, Zhou Haoming, Su Wantong, Liu Zheng, Wang Mingming, Lu Ling
School of Medicine, Southeast University, Nanjing, China.
Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, The First Affiliated Hospital of Nanjing Medical University, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China.
Cell Death Discov. 2021 Sep 16;7(1):243. doi: 10.1038/s41420-021-00632-8.
Liver fibrosis is a patho-physiological process which can develop into cirrhosis, and hepatic carcinoma without intervention. Our study extensively investigated the mechanisms of lncRNA NEAT1 and miR-139-5p in regulating liver fibrosis progression. Our results demonstrated that the expression of lncRNA NEAT1 was increased and the expression of miR-139-5p was decreased in fibrotic liver tissues. LncRNA NEAT1 could sponge miR-139-5p and promoted hepatic stellate cells (HSCs) activation by directly inhibiting the expression of miR-139-5p. The co-localization of lncRNA NEAT1 with miR-139-5p was shown in the cytosols of activated HSCs. miR-139-5p upregulation could suppress the expression of β-catenin. The overexpression of β-catenin promoted HSCs activation. Moreover, we found that β-catenin could interact with SOX9 promoted HSCs activation. Our further studies demonstrated that SOX9 could bind with the TGF-β1 promoter and promoted the transcription activity of TGF-β1. The upregulation of TGF-β1 further promoted HSCs activation. In vivo study also suggested that lncRNA NEAT1 knockdown and miR-139-5p overexpression alleviated murine liver fibrosis. LncRNA NEAT1 exacerbated liver fibrosis by suppressing the expression of miR-139-5p. Collectively, our study suggested that miR-139-5p sponged by lncRNA NEAT1 regulated liver fibrosis via targeting β-catenin/SOX9/TGF-β1 Pathway.
肝纤维化是一种病理生理过程，若不加以干预，可发展为肝硬化和肝癌。我们的研究广泛探讨了lncRNA NEAT1和miR-139-5p在调节肝纤维化进展中的机制。我们的结果表明，在纤维化肝组织中lncRNA NEAT1的表达增加，而miR-139-5p的表达降低。lncRNA NEAT1可以吸附miR-139-5p，并通过直接抑制miR-139-5p的表达来促进肝星状细胞（HSCs）的激活。在活化的HSCs胞质溶胶中显示了lncRNA NEAT1与miR-139-5p的共定位。miR-139-5p的上调可以抑制β-连环蛋白的表达。β-连环蛋白的过表达促进HSCs的激活。此外，我们发现β-连环蛋白可以与SOX9相互作用促进HSCs的激活。我们的进一步研究表明，SOX9可以与TGF-β1启动子结合并促进TGF-β1的转录活性。TGF-β1的上调进一步促进HSCs的激活。体内研究还表明，lncRNA NEAT1的敲低和miR-139-5p的过表达可减轻小鼠肝纤维化。lncRNA NEAT1通过抑制miR-139-5p的表达加剧肝纤维化。总体而言，我们的研究表明，lncRNA NEAT1吸附的miR-139-5p通过靶向β-连环蛋白/SOX9/TGF-β1通路调节肝纤维化。
