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.

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.