Department of Oncology, Panyu Central Hospital, Guangzhou, Guangdong Province, China.
Cancer Institute of Panyu, Guangzhou, Guangdong Province, China.
PeerJ. 2022 May 24;10:e13402. doi: 10.7717/peerj.13402. eCollection 2022.
Neural precursor cell expressed developmentally down-regulated 4-like protein (NEDD4L), an E3 ubiquitin ligase, exerts an important role in diverse biological processes including development, tumorigenesis, and tumor progression. Although the role of NEDD4L in the pathogenesis of lung adenocarcinoma (LUAD) has been described, the mechanism by which NEDD4L promotes LUAD progression remains poorly understood. In the study, the correlation between NEDD4L level and clinical outcome in LUAD patients was analysed using the data from The Cancer Genome Atlas (TCGA) database. NEDD4L expression in LUAD cell lines and tissue samples was assessed through quantitative real-time PCR (qRT-PCR). The biological function of NEDD4L on regulating LUAD cell proliferation was tested with Cell Counting Kit-8 (CCK-8) assay , and mouse xenograft tumor model . We found that NEDD4L expression was significantly decreased in LUAD tissues and cell lines. Lower expression of NEDD4L exhibited a significantly poorer overall survival. Functionally, NEDD4L knockdown in H1299 cells accelerated cell growth, whereas NEDD4L overexpression in A549 cells repressed cell proliferation. NEDD4L overexpression also inhibited tumor xenograft growth . Mechanistically, NEDD4L decreased the protein stability of notch receptor 2 (Notch2) through facilitating its ubiquitination and degradation by ubiquitin-proteasome system. Consequently, NEDD4L negatively regulated Notch signaling activation in LUAD cells, and RO4929097 (a Notch inhibitor) treatment effectively repressed the effect of NEDD4L knockdown on LUAD cell proliferation. Taken together, these results demonstrate that down-regulated NEDD4L facilitates LUAD progression by activating Notch signaling, and NEDD4L may be a promising target to treat LUAD.
神经前体细胞表达的发育下调蛋白 4 样蛋白（NEDD4L）是一种 E3 泛素连接酶，在包括发育、肿瘤发生和肿瘤进展在内的多种生物学过程中发挥着重要作用。尽管已经描述了 NEDD4L 在肺腺癌（LUAD）发病机制中的作用，但 NEDD4L 促进 LUAD 进展的机制仍知之甚少。在这项研究中，使用来自癌症基因组图谱（TCGA）数据库的数据分析了 NEDD4L 水平与 LUAD 患者临床结局之间的相关性。通过实时定量 PCR（qRT-PCR）评估 LUAD 细胞系和组织样本中的 NEDD4L 表达。通过细胞计数试剂盒-8（CCK-8）测定和小鼠异种移植肿瘤模型来测试 NEDD4L 对调节 LUAD 细胞增殖的生物学功能。我们发现 NEDD4L 在 LUAD 组织和细胞系中的表达显著降低。NEDD4L 表达水平较低的患者总生存期明显较差。功能上，NEDD4L 在 H1299 细胞中的敲低加速了细胞生长，而在 A549 细胞中的过表达抑制了细胞增殖。NEDD4L 的过表达也抑制了肿瘤异种移植的生长。机制上，NEDD4L 通过促进其泛素化和通过泛素-蛋白酶体系统降解，降低了 Notch 受体 2（Notch2）的蛋白稳定性。因此，NEDD4L 负调控 LUAD 细胞中的 Notch 信号激活，而 Notch 抑制剂 RO4929097 的处理有效抑制了 NEDD4L 敲低对 LUAD 细胞增殖的影响。总之，这些结果表明，下调的 NEDD4L 通过激活 Notch 信号促进 LUAD 的进展，NEDD4L 可能是治疗 LUAD 的有前途的靶点。
