Hydrogen peroxide promotes epithelial to mesenchymal transition and stemness in human malignant mesothelioma cells

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-1α) and transforming growth factor beta 1 (TGF-β1). 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.