Abstract
Exposure of humans to inorganic arsenic can cause skin cancer. The epithelial–mesenchymal transition (EMT) and acquisition of cancer stem cell (CSC)-like properties are essential steps in the initiation of human skin cancers; however, the mechanisms of action remain obscure. We have found that, during the neoplastic transformation induced by a low concentration (1.0 μM) of arsenite in human keratinocyte HaCaT cells, the cells undergo an EMT and then acquire a malignant CSC-like phenotype. With longer times for transformation of HaCaT cells, there were increased activations of IκB kinase β (IKKβ), inhibitor nuclear factor-kappa B alpha (IκBα), and nuclear factor κB (NF-κB) RelA and increases in the level of Snail. Further, during the transformation of HaCaT cells, the activation of NF-κB RelA up-regulated Snail levels. Inhibition of NF-κB RelA blocked the arsenite-induced EMT, acquisition of a CSC-like phenotype, and neoplastic transformation. These observations show that EMT, along with acquisition of a CSC-like phenotype mediated by IKKβ/IκBα/RelA signal pathway via Snail, contributes to a low concentration of arsenite-induced tumorigenesis.
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Acknowledgments
The authors wish to thank Donald L. Hill (University of Alabama at Birmingham, USA) for editing. This work was supported by the Natural Science Foundations of China (30872146 and 81072327), the Research Fund for the Doctoral Program of Higher Education of China (20103234110005), the Key Program of Educational Commission of Jiangsu Province of China (11KJA330002), and a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (2010).
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The authors declare they have no competing financial interests.
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Rongrong Jiang and Yuan Li contributed equally to this work.
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Jiang, R., Li, Y., Xu, Y. et al. EMT and CSC-like properties mediated by the IKKβ/IκBα/RelA signal pathway via the transcriptional regulator, Snail, are involved in the arsenite-induced neoplastic transformation of human keratinocytes. Arch Toxicol 87, 991–1000 (2013). https://doi.org/10.1007/s00204-012-0933-0
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DOI: https://doi.org/10.1007/s00204-012-0933-0