NELL2 suppresses epithelial-mesenchymal transition and induces ferroptosis via notch signaling pathway in HCC
Abstract Although various malignant tumors have been associated with the aberrant expression of Neural Epidermal Growth Factor-Like 2 (NELL2), its involvement in hepatocellular carcinoma (HCC) has not been previously documented. In this study, NELL2, recognized as a crucial tumor-suppressor gene, wa...
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Nature Portfolio
2025-03-01
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| Series: | Scientific Reports |
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| Online Access: | https://doi.org/10.1038/s41598-025-94669-9 |
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| author | Shiqi Liu Haomin Wu Pengjie Zhang Haonan Zhou Di Wu Yifan Jin Hongwei Yang Ruilin Xing Yubo Wu Gang Wu |
| author_facet | Shiqi Liu Haomin Wu Pengjie Zhang Haonan Zhou Di Wu Yifan Jin Hongwei Yang Ruilin Xing Yubo Wu Gang Wu |
| author_sort | Shiqi Liu |
| collection | DOAJ |
| description | Abstract Although various malignant tumors have been associated with the aberrant expression of Neural Epidermal Growth Factor-Like 2 (NELL2), its involvement in hepatocellular carcinoma (HCC) has not been previously documented. In this study, NELL2, recognized as a crucial tumor-suppressor gene, was found to be infrequently expressed in HCC. In vitro experiments demonstrated that the overexpression of NELL2 significantly inhibited the proliferation, migration, and invasion of liver cancer cells, whereas the suppression of NELL2 markedly enhanced these oncogenic properties. Further investigation revealed that NELL2 impedes epithelial-mesenchymal transition (EMT) via the Notch signaling pathway. Inhibition of the Notch pathway reversed the increased tumor proliferation, migration, and invasion observed following the downregulation of NELL2 expression. Notably, gene enrichment analysis and in vitro studies indicated that NELL2 effectively induced ferroptosis in HCC cells, as evidenced by increased levels of cellular malondialdehyde (MDA), iron, and Reactive Oxygen Species (ROS), alongside decreased glutathione (GSH) levels. The blockade of the Notch signaling pathway substantially diminished NELL2’s capacity to induce ferroptosis. In summary, our findings suggest that NELL2 modulates the Notch signaling pathway to inhibit EMT and promote ferroptosis. Consequently, NELL2 may serve as a novel therapeutic target, potentially functioning as a tumor suppressor gene in HCC. |
| format | Article |
| id | doaj-art-002c8e2386ae4859bf8d86ba32f6e2fa |
| institution | DOAJ |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj-art-002c8e2386ae4859bf8d86ba32f6e2fa2025-08-20T02:49:26ZengNature PortfolioScientific Reports2045-23222025-03-0115111510.1038/s41598-025-94669-9NELL2 suppresses epithelial-mesenchymal transition and induces ferroptosis via notch signaling pathway in HCCShiqi Liu0Haomin Wu1Pengjie Zhang2Haonan Zhou3Di Wu4Yifan Jin5Hongwei Yang6Ruilin Xing7Yubo Wu8Gang Wu9Hepatobiliary Surgery Department, First Hospital of China Medical UniversityHepatobiliary Surgery Department, First Hospital of China Medical UniversityHepatobiliary Surgery Department, First Hospital of China Medical UniversityHepatobiliary Surgery Department, First Hospital of China Medical UniversityHepatobiliary Surgery Department, First Hospital of China Medical UniversityHepatobiliary Surgery Department, First Hospital of China Medical UniversityHepatobiliary Surgery Department, First Hospital of China Medical UniversityHepatobiliary Surgery Department, First Hospital of China Medical UniversityHepatobiliary Surgery Department, First Hospital of China Medical UniversityHepatobiliary Surgery Department, First Hospital of China Medical UniversityAbstract Although various malignant tumors have been associated with the aberrant expression of Neural Epidermal Growth Factor-Like 2 (NELL2), its involvement in hepatocellular carcinoma (HCC) has not been previously documented. In this study, NELL2, recognized as a crucial tumor-suppressor gene, was found to be infrequently expressed in HCC. In vitro experiments demonstrated that the overexpression of NELL2 significantly inhibited the proliferation, migration, and invasion of liver cancer cells, whereas the suppression of NELL2 markedly enhanced these oncogenic properties. Further investigation revealed that NELL2 impedes epithelial-mesenchymal transition (EMT) via the Notch signaling pathway. Inhibition of the Notch pathway reversed the increased tumor proliferation, migration, and invasion observed following the downregulation of NELL2 expression. Notably, gene enrichment analysis and in vitro studies indicated that NELL2 effectively induced ferroptosis in HCC cells, as evidenced by increased levels of cellular malondialdehyde (MDA), iron, and Reactive Oxygen Species (ROS), alongside decreased glutathione (GSH) levels. The blockade of the Notch signaling pathway substantially diminished NELL2’s capacity to induce ferroptosis. In summary, our findings suggest that NELL2 modulates the Notch signaling pathway to inhibit EMT and promote ferroptosis. Consequently, NELL2 may serve as a novel therapeutic target, potentially functioning as a tumor suppressor gene in HCC.https://doi.org/10.1038/s41598-025-94669-9HCCNELL2Notch pathwayEMTFerroptosis |
| spellingShingle | Shiqi Liu Haomin Wu Pengjie Zhang Haonan Zhou Di Wu Yifan Jin Hongwei Yang Ruilin Xing Yubo Wu Gang Wu NELL2 suppresses epithelial-mesenchymal transition and induces ferroptosis via notch signaling pathway in HCC Scientific Reports HCC NELL2 Notch pathway EMT Ferroptosis |
| title | NELL2 suppresses epithelial-mesenchymal transition and induces ferroptosis via notch signaling pathway in HCC |
| title_full | NELL2 suppresses epithelial-mesenchymal transition and induces ferroptosis via notch signaling pathway in HCC |
| title_fullStr | NELL2 suppresses epithelial-mesenchymal transition and induces ferroptosis via notch signaling pathway in HCC |
| title_full_unstemmed | NELL2 suppresses epithelial-mesenchymal transition and induces ferroptosis via notch signaling pathway in HCC |
| title_short | NELL2 suppresses epithelial-mesenchymal transition and induces ferroptosis via notch signaling pathway in HCC |
| title_sort | nell2 suppresses epithelial mesenchymal transition and induces ferroptosis via notch signaling pathway in hcc |
| topic | HCC NELL2 Notch pathway EMT Ferroptosis |
| url | https://doi.org/10.1038/s41598-025-94669-9 |
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