NEDD4L-induced β-catenin ubiquitination suppresses the formation and progression of interstitial pulmonary fibrosis via inhibiting the CTHRC1/HIF-1α axis.
NEDD4L-induced β-catenin ubiquitination suppresses the formation and progression of interstitial pulmonary fibrosis via inhibiting the CTHRC1/HIF-1α axis.
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DOI：
10.7150/ijbs.57247
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发表时间：
2021
影响因子：
9.2
通讯作者：
Zou J
中科院分区：
文献类型：
--
作者：
Chen L;Yang Y;Yan H;Peng X;Zou J
间质性肺纤维化（IPF）是一种严重的进行性肺疾病，治疗选择有限，预后差。我们首先在IPF相关表达微阵列数据集中发现了神经前体细胞表达发育下调4样蛋白（NEDD4L）的下调水平，因此本研究旨在探讨NEDD4L在IPF中的分子机制。随后在IPF患者肺组织和小鼠模型中验证了NEDD4L的表达。然后，收集小鼠原代肺成纤维细胞（LFs）进行体外功能实验，使用CCK-8， Transwell和免疫荧光法检测LFs的活力，迁移和分化。在体内小鼠模型中进一步评估了体外研究结果。NEDD4L在IPF患者及小鼠肺组织中表达下调。NEDD4L的过表达限制了小鼠IPF的形成和进展，减弱了lf的增殖、侵袭和分化能力。此外，NEDD4L通过增强β-catenin泛素化和下调CTHRC1/HIF-1α轴来阻止LFs的活性。体内实验也验证了NEDD4L沉默可抑制β-catenin泛素化，激活CTHRC1/HIF-1α轴，从而加重小鼠IPF。NEDD4L可能通过增强β-catenin泛素化和抑制CTHRC1/HIF-1α轴抑制IPF的形成和进展。
Interstitial pulmonary fibrosis (IPF) is a severe progressive lung disease with limited therapeutic options and poor prognosis. Initially, we found the downregulated level of neural precursor cell expressed developmentally down-regulated 4-like protein (NEDD4L) in IPF-related expression microarray dataset, and this study was thus performed to explore the molecular mechanism of NEDD4L in IPF. The expression of NEDD4L was subsequently validated in lung tissues of IPF patients and mouse models. Then, mouse primary lung fibroblasts (LFs) were collected for in vitro functional experiments, with CCK-8, Transwell, and immunofluorescence assays used to examine the viability, migration, and differentiation of LFs. The in vitro findings were further assessed using in vivo mouse models. The expression of NEDD4L was down-regulated in lung tissues of IPF patients and mouse models. Overexpression of NEDD4L restricted the formation and progression of IPF in mice and attenuated the proliferative, invasive and differentiative abilities of LFs. Further, NEDD4L halted LFs activity by enhancing β-catenin ubiquitination and down-regulating the CTHRC1/HIF-1α axis. Also, in vivo experiments then validated that NEDD4L silencing repressed β-catenin ubiquitination and activated the CTHRC1/HIF-1α axis, thereby aggravating IPF in mice. NEDD4L may suppress the formation and progression of IPF through augmenting β-catenin ubiquitination and inhibiting the CTHRC1/HIF-1α axis.
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