Upregulation of LncRNA Malat1 Induced Proliferation and Migration of Airway Smooth Muscle Cells via miR-150-eIF4E/Akt Signaling
Upregulation of LncRNA Malat1 Induced Proliferation and Migration of Airway Smooth Muscle Cells via miR-150-eIF4E/Akt Signaling
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LncRNA Malat1 通过 miR-150-eIF4E/Akt 信号传导上调诱导气道平滑肌细胞增殖和迁移
DOI：
10.3389/fphys.2019.01337
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发表时间：
2019-10-22
影响因子：
4
通讯作者：
Han, Wei
中科院分区：
文献类型：
--
作者：
Lin, Li;Li, Qinghai;Han, Wei
气道平滑肌细胞(ASMC)的增殖和迁移增加是哮喘气道重塑形成的关键过程。长非编码RNAs(Long Non-Coding RNAs，LncRNAs)是多种生理和病理过程的关键介质，参与包括哮喘在内的多种疾病的发病机制。LncRNA MALAT1被广泛报道调节多种细胞类型的增殖和迁移，并参与多种人类疾病的发病机制。然而，目前尚不清楚MALAT1是否调节ASMC的增殖和迁移。在此，我们探讨了MALAT1在血小板衍生生长因子BB(PDGF-BB)刺激的ASMC增殖和迁移中的作用及其可能的分子机制。结果显示，经PDGF-BB处理的ASMC中MALAT1表达显著上调，MALAT1基因表达下调可有效抑制PDGF-BB诱导的ASMC增殖和迁移。我们的数据还表明，miR-150是MALAT1在ASMC中的靶点，并抑制PDGF-BB诱导的ASMC增殖和迁移，而MALAT1的过表达有效地逆转了这种抑制作用。此外，Akt信号的重要调节因子翻译起始因子4E(EIF4E)被认为是miR-150的靶点，eIF4E基因敲除和Akt抑制剂GSK690693均可抑制PDGF-BB诱导的ASMC增殖和迁移。总之，这些数据表明，MALAT1作为miR-150的竞争内源性RNA(CerNA)，下调eIF4E的表达并激活Akt信号，从而参与PDGF-BB诱导的ASMC增殖和迁移。这些发现表明，MALAT1基因敲除可能为限制哮喘的气道重塑提供了一个新的靶点。
The increased proliferation and migration of airway smooth muscle cells (ASMCs) are critical processes in the formation of airway remodeling in asthma. Long non-coding RNAs (lncRNAs) have emerged as key mediators of diverse physiological and pathological processes, and are involved in the pathogenesis of various diseases, including asthma. LncRNA Malat1 has been widely reported to regulate the proliferation and migration of multiple cell types and be involved in the pathogenesis of various human diseases. However, it remains unknown whether Malat1 regulates ASMC proliferation and migration. Here, we explored the function of Malat1 in ASMC proliferation and migration in vitro stimulated by platelet-derived growth factor BB (PDGF-BB), and the underlying molecular mechanism involved. The results showed that Malat1 was significantly upregulated in ASMCs treated with PDGF-BB, and knockdown of Malat1 effectively inhibited ASMC proliferation and migration induced by PDGF-BB. Our data also showed that miR-150 was a target of Malat1 in ASMCs, and inhibited PDGF-BB-induced ASMC proliferation and migration, whereas the inhibition effect was effectively reversed by Malat1 overexpression. Additionally, translation initiation factor 4E (eIF4E), an important regulator of Akt signaling, was identified to be a target of miR-150, and both eIF4E knockdown and Akt inhibitor GSK690693 inhibited PDGF-BB-induced ASMC proliferation and migration. Collectively, these data indicate that Malat1, as a competing endogenous RNA (ceRNA) for miR-150, derepresses eIF4E expression and activates Akt signaling, thereby being involved in PDGF-BB-induced ASMC proliferation and migration. These findings suggest that Malat1 knockdown may present a new target to limit airway remodeling in asthma.