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. 2013 Jun;87(6):991-1000. doi: 10.1007/s00204-012-0933-0. Epub 2012 Oct 16.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arsenites / toxicity*
  • Carcinogens / toxicity*
  • Cell Line
  • Cell Transformation, Neoplastic / chemically induced*
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / pathology
  • Epithelial-Mesenchymal Transition / drug effects*
  • Humans
  • I-kappa B Kinase / metabolism*
  • I-kappa B Proteins / metabolism*
  • Keratinocytes / drug effects*
  • Keratinocytes / enzymology
  • Keratinocytes / pathology
  • NF-KappaB Inhibitor alpha
  • Neoplastic Stem Cells / drug effects*
  • Neoplastic Stem Cells / enzymology
  • Neoplastic Stem Cells / pathology
  • Phenotype
  • Signal Transduction / drug effects
  • Snail Family Transcription Factors
  • Sodium Compounds / toxicity*
  • Time Factors
  • Transcription Factor RelA / metabolism*
  • Transcription Factors / metabolism*


  • Arsenites
  • Carcinogens
  • I-kappa B Proteins
  • NFKBIA protein, human
  • RELA protein, human
  • Snail Family Transcription Factors
  • Sodium Compounds
  • Transcription Factor RelA
  • Transcription Factors
  • NF-KappaB Inhibitor alpha
  • sodium arsenite
  • I-kappa B Kinase
  • IKBKB protein, human