Down-regulated NEDD4L facilitates tumor progression through activating Notch signaling in lung adenocarcinoma
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...
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PeerJ Inc.
2022-05-01
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| author | Liping Lin Xuan Wu Yuanxue Jiang Caijiu Deng Xi Luo Jianjun Han Jiazhu Hu Xiaolong Cao |
| author_facet | Liping Lin Xuan Wu Yuanxue Jiang Caijiu Deng Xi Luo Jianjun Han Jiazhu Hu Xiaolong Cao |
| author_sort | Liping Lin |
| collection | DOAJ |
| description | 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 in vitro, and mouse xenograft tumor model in vivo. 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 in vivo. 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. |
| first_indexed | 2024-03-09T07:02:27Z |
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| language | English |
| last_indexed | 2024-03-09T07:02:27Z |
| publishDate | 2022-05-01 |
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| spelling | doaj.art-b151c486091f402a96312ecba1ace6302023-12-03T09:49:23ZengPeerJ Inc.PeerJ2167-83592022-05-0110e1340210.7717/peerj.13402Down-regulated NEDD4L facilitates tumor progression through activating Notch signaling in lung adenocarcinomaLiping Lin0Xuan Wu1Yuanxue Jiang2Caijiu Deng3Xi Luo4Jianjun Han5Jiazhu Hu6Xiaolong Cao7Department of Oncology, Panyu Central Hospital, Guangzhou, Guangdong Province, ChinaDepartment of Oncology, Peking University Shenzhen Hospital, Shenzhen, Guangdong Province, ChinaDepartment of Oncology, Panyu Central Hospital, Guangzhou, Guangdong Province, ChinaDepartment of Oncology, Panyu Central Hospital, Guangzhou, Guangdong Province, ChinaDepartment of Oncology, Panyu Central Hospital, Guangzhou, Guangdong Province, ChinaDepartment of Oncology, Panyu Central Hospital, Guangzhou, Guangdong Province, ChinaDepartment of Oncology, Panyu Central Hospital, Guangzhou, Guangdong Province, ChinaDepartment of Oncology, Panyu Central Hospital, Guangzhou, Guangdong Province, ChinaNeural 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 in vitro, and mouse xenograft tumor model in vivo. 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 in vivo. 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.https://peerj.com/articles/13402.pdfLung adenocarcinomaNEDD4LNotch2Hes1RO4929097 |
| spellingShingle | Liping Lin Xuan Wu Yuanxue Jiang Caijiu Deng Xi Luo Jianjun Han Jiazhu Hu Xiaolong Cao Down-regulated NEDD4L facilitates tumor progression through activating Notch signaling in lung adenocarcinoma PeerJ Lung adenocarcinoma NEDD4L Notch2 Hes1 RO4929097 |
| title | Down-regulated NEDD4L facilitates tumor progression through activating Notch signaling in lung adenocarcinoma |
| title_full | Down-regulated NEDD4L facilitates tumor progression through activating Notch signaling in lung adenocarcinoma |
| title_fullStr | Down-regulated NEDD4L facilitates tumor progression through activating Notch signaling in lung adenocarcinoma |
| title_full_unstemmed | Down-regulated NEDD4L facilitates tumor progression through activating Notch signaling in lung adenocarcinoma |
| title_short | Down-regulated NEDD4L facilitates tumor progression through activating Notch signaling in lung adenocarcinoma |
| title_sort | down regulated nedd4l facilitates tumor progression through activating notch signaling in lung adenocarcinoma |
| topic | Lung adenocarcinoma NEDD4L Notch2 Hes1 RO4929097 |
| url | https://peerj.com/articles/13402.pdf |
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