Department of Pulmonary and Critical Care Medicine, Shanghai Fifth People's Hospital, Fudan University, Shanghai 200240, China.
Department of Pulmonary and Critical Care Medicine, Shanghai Fifth People's Hospital, Fudan University, Shanghai 200240, China.
Int Immunopharmacol. 2022 Oct;111:109086. doi: 10.1016/j.intimp.2022.109086. Epub 2022 Jul 27.
Smoking is an essential facet of the pathogenesis of chronic obstructive pulmonary disease (COPD), which is typically characterized by inflammation and cellular senescence of alveolar epithelial cells. In this study, we investigated the function and fundamental mechanism of a novel circular RNA XPO1 (circXPO1) in cigarette smoke (CS)-induced inflammation and cellular senescence of alveolar epithelial cells. We found that circXPO1 was overexpressed in the lungs of CS-exposed mice and the CS extract (CSE)-treated alveolar epithelial cell line MLE12. Suppression of circXPO1 inhibited CSE-induced inflammatory cytokine production and cellular senescence. In vivo assays also demonstrated that circXPO1 knockdown attenuates CS-induced inflammation and senescence in the mouse lungs. Mechanistically, circXPO1 can directly bind to miR-23b-3p, preventing miR-23b-3p from binding to its target TGF-β-activated kinase 1/MAP3K7 binding protein 3 (TAB3)mRNA. In addition, under CSE conditions, miR-23b-3p overexpression recapitulated the prophylactic effects of circXPO1 knockdown. Inhibition of miR-23b-3p attenuated the function of circXPO1 knockdown in CSE-treated MLE12 cells. These results reveal that circXPO1 plays a role in the pathogenesis of COPD by modulating TAB3 through sponging miR-23b-3p.
吸烟是慢性阻塞性肺疾病（COPD）发病机制的一个重要方面，COPD 通常以肺泡上皮细胞的炎症和细胞衰老为特征。在这项研究中，我们研究了新型环状 RNA XPO1（circXPO1）在香烟烟雾（CS）诱导的肺泡上皮细胞炎症和细胞衰老中的功能和基本机制。我们发现 circXPO1 在 CS 暴露的小鼠肺部和 CS 提取物（CSE）处理的肺泡上皮细胞系 MLE12 中过表达。circXPO1 的抑制抑制了 CSE 诱导的炎症细胞因子产生和细胞衰老。体内实验也表明 circXPO1 敲低可减轻 CS 诱导的小鼠肺部炎症和衰老。机制上，circXPO1 可以直接与 miR-23b-3p 结合，阻止 miR-23b-3p 与其靶基因 TGF-β激活激酶 1/MAP3K7 结合蛋白 3（TAB3）mRNA 结合。此外，在 CSE 条件下，miR-23b-3p 的过表达再现了 circXPO1 敲低的预防作用。抑制 miR-23b-3p 减弱了 CSE 处理的 MLE12 细胞中 circXPO1 敲低的功能。这些结果表明，circXPO1 通过海绵吸附 miR-23b-3p 来调节 TAB3，从而在 COPD 的发病机制中发挥作用。
