Department of Lung Disease, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong, 250011, People's Republic of China.
Department of Traditional Chinese Medicine, Shandong Academy of Occupational Health and Occupational Medicine, Shandong Academy of Medical Sciences, Jinan, Shandong, 250062, People's Republic of China.
Cell Death Dis. 2019 Feb 12;10(2):129. doi: 10.1038/s41419-019-1339-1.
Long non-coding RNAs (lncRNAs) have been reported to be involved in various pathophysiological processes in many diseases. However, the role and mechanism of lncRNAs in pulmonary fibrosis have not been explicitly delineated. In the present study, we found that lncRNA ZEB1 antisense RNA 1 (ZEB1-AS1) is upregulated in the lungs of BLM-induced rats and TGF-β1-induced RLE-6TN cells, and positively correlated with the levels of ZEB1, an epithelial-mesenchymal transition (EMT) master regulator. Knockdown of ZEB1-AS1 alleviated BLM-induced fibrogenesis, in vivo, via inhibiting EMT progress. Mechanistically, we identified that ZEB1-AS1 promoted fibrogenesis in RLE-6TN cells and ZEB1-AS1 silencing inhibited TGF-β1-induced fibrogenesis through modulation of miR-141-3p. Further experiments revealed that ZEB1-AS1 acted as competing endogenous RNA (ceRNA) of miR-141-3p: forced expression of ZEB1-AS1 reduced the expression of miR-141-3p to activate Zinc-finger Ebox Binding Homeobox 1 (ZEB1) in RLE-6TN cells. In addition, we found that upregulation of miR-141-3p prevented fibrogenesis by targeting ZEB1. Therefore, our finding suggested lncRNA ZEB1-AS1 as a new profibrotic molecule that acts as a regulator of miR-141-3p/ZEB1 axis during lung fibrosis and demonstrated ZEB1-AS1 as a potential therapeutic target for the prevention and treatment of pulmonary fibrosis.
长链非编码 RNA（lncRNA）已被报道参与多种疾病的各种病理生理过程。然而，lncRNA 在肺纤维化中的作用和机制尚未明确阐述。在本研究中，我们发现 lncRNA ZEB1 反义 RNA 1（ZEB1-AS1）在博来霉素诱导的大鼠和 TGF-β1 诱导的 RLE-6TN 细胞的肺部中上调，并且与上皮-间充质转化（EMT）主调控因子 ZEB1 的水平呈正相关。ZEB1-AS1 的敲低通过抑制 EMT 进展，在体内减轻 BLM 诱导的纤维化。在机制上，我们确定 ZEB1-AS1 促进 RLE-6TN 细胞中的纤维化，并且 ZEB1-AS1 沉默通过调节 miR-141-3p 抑制 TGF-β1 诱导的纤维化。进一步的实验表明，ZEB1-AS1 作为 miR-141-3p 的竞争性内源 RNA（ceRNA）起作用：强制表达 ZEB1-AS1 降低了 miR-141-3p 的表达，从而在 RLE-6TN 细胞中激活锌指 E 框结合同源盒 1（ZEB1）。此外，我们发现 miR-141-3p 的上调通过靶向 ZEB1 防止纤维化。因此，我们的发现表明 lncRNA ZEB1-AS1 作为一种新的促纤维化分子，在肺纤维化过程中作为 miR-141-3p/ZEB1 轴的调节剂起作用，并证明 ZEB1-AS1 是预防和治疗肺纤维化的潜在治疗靶点。
Zotero 插件
