Hydrogen Peroxide Promotes Epithelial to Mesenchymal Transition and Stemness in Human Malignant Mesothelioma Cells
Hydrogen Peroxide Promotes Epithelial to Mesenchymal Transition and Stemness in Human Malignant Mesothelioma Cells
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DOI：
10.7314/apjcp.2013.14.6.3625
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发表时间：
2013-01-01
影响因子：
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通讯作者：
Kim, Yongbaek
中科院分区：
文献类型：
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作者：
Kim, Myung-Chul;Cui, Feng-Ji;Kim, Yongbaek
已知活性氧（ROS）促进与石棉纤维和炎症密切相关的间皮癌发生。上皮细胞向间充质细胞转化（EMT）是参与肿瘤进展的重要过程，为癌细胞提供侵袭性。本研究是为了确定是否EMT是由过氧化氢诱导的人恶性间皮瘤（HMM）细胞。用H2 O2处理培养的HMM细胞，然后测量EMT相关基因和蛋白的表达水平。免疫组化显示，TWIST 1表达仅限于HMM组织中的肉瘤细胞，而非上皮样细胞。用H2 O2处理HMM细胞促进EMT，如波形蛋白、SLUG和TWIST 1的表达水平增加和E-钙粘蛋白表达降低所示。用H2 O2处理HMM细胞也显著增加了干性基因如OCT 4、SOX 2和NANOG的表达。这些基因的改变通过缺氧诱导因子1 α（HIF-1 α）和转化生长因子β 1（TGF-β 1）的激活介导。考虑到用H2 O2处理导致过量的ROS，本研究表明氧化应激可能通过促进EMT过程和增强干性基因的表达在HMM致癌中起关键作用。
Reactive oxygen species (ROS) are known to promote mesothelial carcinogenesis that is closely associated with asbestos fibers and inflammation. Epithelial to mesenchymal cell transition (EMT) is an important process involved in the progression of tumors, providing cancer cells with aggressiveness. The present study was performed to determine if EMT is induced by H2O2 in human malignant mesothelioma (HMM) cells. Cultured HMM cells were treated with H2O2, followed by measuring expression levels of EMT-related genes and proteins. Immunohistochemically, TWIST1 expression was confined to sarcomatous cells in HMM tissues, but not in epithelioid cells. Treatment of HMM cells with H2O2 promoted EMT, as indicated by increased expression levels of vimentin, SLUG and TWIST1, and decreased E-cadherin expression. Expression of stemness genes such as OCT4, SOX2 and NANOG was also significantly increased by treatment of HMM cells with H2O2. Alteration of these genes was mediated via activation of hypoxia inducible factor 1 alpha (HIF-1 alpha) and transforming growth factor beta 1 (TGF-beta 1). Considering that treatment with H2O2 results in excess ROS, the present study suggests that oxidative stress may play a critical role in HMM carcinogenesis by promoting EMT processes and enhancing the expression of stemness genes.