Abstract：
Asthma is a chronic respiratory disease characterized by airway inflammation and remodeling. Epithelial-mesenchymal transition (EMT) of bronchial epithelial cells is considered to be a crucial player in asthma. Methyltransferase-like 14 (METTL14), an RNA methyltransferase, is implicated in multiple pathological processes, including EMT, cell proliferation and migration. However, the role of METTL14 in asthma remains uncertain. This research aimed to explore the biological functions of METTL14 in asthma and its underlying upstream mechanisms. METTL14 expression was down-regulated in asthmatic from three GEO datasets (GSE104468, GSE165934, and GSE74986). Consistent with this trend, METTL14 was decreased in the lung tissues of OVA-induced asthmatic mice and transforming growth factor-β1 (TGF-β1)-stimulated human bronchial epithelial cells (Beas-2B) in this study. Overexpression of METTL14 caused reduction in mesenchymal markers (FN1, N-cad, Col-1 and α-SMA) in TGF-β1-treated cells, but caused increase in epithelial markers (E-cad), thus inhibiting EMT. Also, METTL14 suppressed the proliferation and migration ability of TGF-β1-treated Beas-2B cells. Two transcription factors, ETS1 and RBPJ, could both bind to the promoter region of METTL14 and drive its expression. Elevating METTL14 expression could reversed EMT, cell proliferation and migration promoted by ETS1 or RBPJ deficiency. These results indicate that the ETS1/METTL14 and RBPJ/METTL14 transcription axes exhibit anti-EMT, anti-proliferation and anti-migration functions in TGF-β1-induced bronchial epithelial cells, implying that METTL14 may be considered an alternative candidate target for the treatment of asthma.
摘要：
哮喘是一种以气道炎症和重塑为特征的慢性呼吸道疾病。支气管上皮细胞的上皮-间质转化（EMT）被认为是哮喘的关键参与者。甲基转移酶样14(METTL14)，RNA甲基转移酶,与多种病理过程有关，包括EMT,细胞增殖和迁移。然而,METTL14在哮喘中的作用尚不明确.本研究旨在探讨METTL14在哮喘中的生物学功能及其潜在的上游机制。来自三个GEO数据集(GSE104468、GSE165934和GSE74986)的哮喘患者的METTL14表达下调。与这一趋势一致,在这项研究中，OVA诱导的哮喘小鼠的肺组织和转化生长因子-β1（TGF-β1）刺激的人支气管上皮细胞（Beas-2B）中的METTL14降低。METTL14的过表达导致间充质标志物的减少（FN1，N-cad，Col-1和α-SMA）在TGF-β1处理的细胞中，但导致上皮标志物（E-cad）增加，从而抑制EMT。此外，METTL14抑制TGF-β1处理的Beas-2B细胞的增殖和迁移能力。两个转录因子，ETS1和RBPJ，可以结合到METTL14的启动子区域并驱动其表达。升高METTL14表达可以逆转EMT，ETS1或RBPJ缺乏促进细胞增殖和迁移。这些结果表明，ETS1/METTL14和RBPJ/METTL14转录轴表现出抗EMT，TGF-β1诱导的支气管上皮细胞的抗增殖和抗迁移功能，这意味着METTL14可能被认为是治疗哮喘的替代候选靶点。
