The p53/RMRP/miR122 signaling loop promotes epithelial-mesenchymal transition during the development of silica-induced lung fibrosis by activating the notch pathway
The p53/RMRP/miR122 signaling loop promotes epithelial-mesenchymal transition during the development of silica-induced lung fibrosis by activating the notch pathway
复制标题
p53/RMRP/miR122信号环路通过激活Notch通路促进二氧化硅诱导的肺纤维化发展过程中的上皮-间质转化
DOI：
10.1016/j.chemosphere.2020.128133
复制
发表时间：
2021-01-01
期刊：
影响因子：
8.8
通讯作者：
Zhou, Pingkun
中科院分区：
文献类型：
--
作者：
Huang, Ruixue;Bai, Chenjun;Zhou, Pingkun
背景：了解长非编码RNA(LncRNAs)在EMT中的作用将有助于建立新的途径，进一步揭示肺纤维化的机制，并确定预防和治疗的靶点。本研究旨在鉴定二氧化硅诱导的特异性lncRNAs，并研究其上下游基因之间的反馈环调控。方法和材料：采用基因芯片检测、实时定量聚合酶链式反应和Western印迹分析、双荧光素酶报告基因活性检测和染色质免疫沉淀检测。结果：染矽尘小鼠肺组织线粒体RNA加工内切核糖核酸酶(RMRP)的RNA组分和P53的表达均显著上调。染矽尘后P53的上调激活了RMRP的表达，从而促进了EMT。当RMRP过度表达时，额外的RMRP就像海绵一样与miR122结合，从而降低miR122的水平。利用微阵列，miR122被确定为P53的潜在上游调控因子。这种关系也通过双荧光素酶报告基因得到了验证。因此，miR122水平降低会导致P53活性增加。更重要的是，RMRP促进Notch 1的转录，进而导致Notch途径的激活。结论：P53/RMRP/miR122反馈环可能通过激活Notch通路参与EMT的发展，这为理解矽肺纤维化的复杂调控网络提供了新的视角。(C)2020爱思唯尔有限公司。保留所有权利。
Background: Understanding the roles of long noncoding RNAs (lncRNAs) in EMT would help with establishing novel avenues for further uncovering the mechanisms of lung fibrosis and identifying preventative and therapeutic targets. This study aimed to identify silica-induced specific lncRNAs and investigate the feedback loop regulation among their upstream and downstream genes.Methods and materials: A microarray assay, quantitative real-time polymerase chain reaction and Western blot analysis dual-luciferase reporter gene activity and chromatin immunoprecipitation assays were used. Moreover, a silica-induced lung fibrosis mouse model was used to verify the roles of the lncRNAs.Results: Following silica exposure, both RNA component of mitochondrial RNA processing endoribonuclease (RMRP) and p53 were significantly upregulated during the EMT. The upregulation of p53 upon silica exposure activated RMRP expression, which promoted the EMT. When RMRP is overexpressed, additional RMRP acts as a sponge to bind to miR122, thus decreasing miR122 levels. Using microarrays, miR122 was identified as a potential upstream regulator of p53. This relationship was also verified using the dual-luciferase reporter gene. Hence, decreased miR122 levels result in an increase in p53 activity. More importantly, RMRP promotes the transcription of Notch 1, which, in turn, results in Notch pathway activation. We show that the p53/RMRP/miR122 pathway creates a positive feedback loop that promotes EMT progress by activating the Notch signaling pathway.Conclusion: Our data indicated that p53/RMRP/miR122 feedback loop might contribute to the EMT development by activating Notch pathway, which provides new sight into understanding of the complex network regulating silica-induced lung fibrosis. (C) 2020 Elsevier Ltd. All rights reserved.