Potential role of ferritin heavy chain in oxidative stress and apoptosis in human mesothelial and mesothelioma cells: implications for asbestos-induced oncogenesis
Potential role of ferritin heavy chain in oxidative stress and apoptosis in human mesothelial and mesothelioma cells: implications for asbestos-induced oncogenesis
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DOI：
10.1093/carcin/bgm090
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发表时间：
2007-09-01
期刊：
影响因子：
4.7
通讯作者：
Saga, Tsuneo
中科院分区：
文献类型：
--
作者：
Aung, Winn;Hasegawa, Sumitaka;Saga, Tsuneo
石棉暴露是恶性间皮瘤（MM）的已知病因。然而，体外细胞培养研究提供了矛盾的证据，石棉暴露于间皮细胞引起细胞毒性或细胞凋亡，而不是恶性转化。虽然已经表明与石棉相关的铁通过产生活性氧（ROS）参与细胞毒性和可能的MM发病机制，但分子机制在很大程度上仍然未知。在这里，我们证明了铁蛋白重链（FHC），铁结合蛋白铁蛋白的核心亚基，作为一种抗凋亡蛋白对有毒石棉和氧化应激在人类间皮瘤细胞和MM细胞。我们发现，FHC在石棉暴露的MeT-5A人间皮细胞中诱导。稳定表达FHC的间皮细胞系在石棉暴露后产生的主要活性氧之一过氧化氢（H2 O2）量更少，并且与空载体转染的细胞相比，对H2 O2诱导的细胞凋亡更耐受。接下来，我们研究了FHC在人MM细胞中的生物学作用。我们发现，NCI-H2052，一种人类MM细胞系，具有比MeT-5A更高的内源性FHC表达，并使用该细胞来解决MM中的FHC功能。与MeT-5A相比，NCI-H2052显示出减少的H2 O2产生和抗肿瘤表型。通过使用FHC小干扰RNA抑制过表达的FHC使MM细胞对凋亡敏感，表明FHC对MM细胞的凋亡抵抗的贡献。我们的研究结果强调了FHC在石棉诱导的间皮瘤发病机制中的潜在作用。
Exposure to asbestos is a known etiological factor in malignant mesothelioma (MM). However, in vitro cell culture studies have provided paradoxical evidence that asbestos exposure to mesothelial cells causes cytotoxicity or apoptosis rather than malignant transformation. Although it has been shown that the iron associated with asbestos participates in the cell toxicity and probably MM pathogenesis via generation of reactive oxygen species (ROS), the molecular mechanisms largely remain unknown. Here, we demonstrate that ferritin heavy chain (FHC), a core subunit of iron-binding protein ferritin, works as an anti-apoptotic protein against toxic asbestos and oxidative stress in human mesothelial cells and MM cells. We found that FHC was induced in asbestos-exposed MeT-5A human mesothelial cells. The mesothelial cell line stably expressing FHC generated less amount of hydrogen peroxide (H2O2), one of the main ROS, after asbestos exposure and was more resistant to apoptosis induced by H2O2 compared with the cells transfected with the empty vector. Next, we investigated biological roles of FHC in human MM cell. We found that NCI-H2052, a human MM cell line, had a higher expression of endogenous FHC than MeT-5A and used the cell to address FHC function in MM. NCI-H2052 showed reduced H2O2 production and an apoptosis-resistant phenotype compared with MeT-5A. Suppression of the over-expressed FHC by using FHC small interfering RNA rendered the MM cells sensitive to apoptosis, suggesting the contribution of FHC to apoptosis resistance of the MM cells. Our findings highlight the potential role of FHC in the pathogenesis of asbestos-induced mesothelioma.