Liu Shiqi, Wu Haomin, Zhang Pengjie, Zhou Haonan, Wu Di, Jin Yifan, Yang Hongwei, Xing Ruilin, Wu Yubo, Wu Gang
Hepatobiliary Surgery Department, First Hospital of China Medical University, No.155, Nanjingbei Street, Shenyang, 110001, Liaoning, People's Republic of China.
Key Laboratory of General Surgery of Liaoning Province, First Hospital of China Medical University, No.155, Nanjingbei Street, Shenyang, 110001, Liaoning Province, People's Republic of China.
Sci Rep. 2025 Mar 25;15(1):10193. doi: 10.1038/s41598-025-94669-9.
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.
尽管多种恶性肿瘤都与神经表皮生长因子样2（NELL2）的异常表达有关，但其在肝细胞癌（HCC）中的作用此前尚未见报道。在本研究中，被认为是关键肿瘤抑制基因的NELL2在HCC中表达稀少。体外实验表明，NELL2的过表达显著抑制肝癌细胞的增殖、迁移和侵袭，而抑制NELL2则明显增强这些致癌特性。进一步研究发现，NELL2通过Notch信号通路阻碍上皮-间质转化（EMT）。抑制Notch通路可逆转NELL2表达下调后观察到的肿瘤增殖、迁移和侵袭增加。值得注意的是，基因富集分析和体外研究表明，NELL2可有效诱导HCC细胞发生铁死亡，表现为细胞丙二醛（MDA）、铁和活性氧（ROS）水平升高，同时谷胱甘肽（GSH）水平降低。Notch信号通路的阻断显著降低了NELL2诱导铁死亡的能力。总之，我们的研究结果表明，NELL2通过调节Notch信号通路来抑制EMT并促进铁死亡。因此，NELL2可能是一种新的治疗靶点，在HCC中可能起到肿瘤抑制基因的作用。
