Zhang Nenghua, Shen Xiaohua, Yu Yunnong, Xu Long, Wang Zheng, Zhu Jia
Department of Experimental Diagnosis, Provincial and Municipal Medical Key Disciplines, Jiaxing University Affiliated Traditional Chinese Medicine Hospital.
School of International and Public Affairs, Shanghai Jiao Tong University.
Environ Health Prev Med. 2025;30:8. doi: 10.1265/ehpm.24-00216.
Lead is a persistent inorganic environmental pollutant with global implication for human health. Among the diseases associated with lead exposure, the damage to the central nervous system has received considerable attention. It has been reported that long-term lead exposure increases the risk of meningioma; however, the underlying mechanism remains poorly understood. Clinical studies have indicated that loss-of-function and mutations in the neurofibromin-2 (NF2) gene play a crucial role in promoting meningioma formation.
The effect of Pb on meningioma were tested in-vitro and in-vivo. Two human meningioma cell lines were used in this study, including NF2-wildtype IOMM-Lee cell and NF2-null CH157-MN cell. Cell viability, cell cycle and cell size were examined after Pb exposure. The expression of Merlin, mammalian sterile 20-like kinases 1 and 2 (MST1/2) and Yes-associated protein (YAP) from these two meningioma cells were analyzed by Western blot. A xenograft mouse model was constructed by subcutaneous injection of IOMM-Lee meningioma cells.
This study demonstrated that treatment with lead induce dose-dependent proliferation in IOMM-Lee cell (with an EC value of 19.6 µM). Moreover, IOMM-Lee cell exhibited augmented cell size in conjunction with elevated levels of phosphorylated histone H3, indicative of altered cell cycle progression resulting from lead exposure. However, no significant change was observed in the CH157-MN cell. Additionally, the Merlin-Hippo signaling pathway was inactivated with decreased Merlin and phosphorylation levels of MST1/2 and YAP, leading to increased YAP nuclear translocation in IOMM-Lee cells. However, there was no change in the Merlin-Hippo signaling pathway in CH157-MN cells after lead treatment. The administration of Pb resulted in an acceleration of the subcutaneous IOMM-Lee meningioma xenograft growth in mice.
Overall, the current study elucidates the potential mechanism by which lead exposure promotes the proliferation of meningioma with NF2 expression for the first time.
铅是一种持久性无机环境污染物，对全球人类健康都有影响。在与铅暴露相关的疾病中，对中枢神经系统的损害受到了相当多的关注。据报道，长期铅暴露会增加患脑膜瘤的风险；然而，其潜在机制仍知之甚少。临床研究表明，神经纤维瘤蛋白2（NF2）基因的功能丧失和突变在促进脑膜瘤形成中起关键作用。
在体外和体内测试铅对脑膜瘤的影响。本研究使用了两个人脑膜瘤细胞系，包括NF2野生型IOMM-Lee细胞和NF2缺失型CH157-MN细胞。铅暴露后检测细胞活力、细胞周期和细胞大小。通过蛋白质免疫印迹分析这两种脑膜瘤细胞中Merlin、哺乳动物不育20样激酶1和2（MST1/2）以及Yes相关蛋白（YAP）的表达。通过皮下注射IOMM-Lee脑膜瘤细胞构建异种移植小鼠模型。
本研究表明，铅处理可诱导IOMM-Lee细胞呈剂量依赖性增殖（EC值为19.6µM）。此外，IOMM-Lee细胞的细胞大小增大，同时磷酸化组蛋白H3水平升高，表明铅暴露导致细胞周期进程改变。然而，CH157-MN细胞未观察到显著变化。此外，Merlin-Hippo信号通路失活，Merlin、MST1/2和YAP的磷酸化水平降低，导致IOMM-Lee细胞中YAP核转位增加。然而，铅处理后CH157-MN细胞中的Merlin-Hippo信号通路没有变化。给予铅导致小鼠皮下IOMM-Lee脑膜瘤异种移植瘤生长加速。
总体而言，本研究首次阐明了铅暴露促进具有NF2表达的脑膜瘤增殖的潜在机制。
