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1337675 
Journal Article 
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 
Jiang, R; Li, Y; Xu, Y; Zhou, Y; Pang, Y; Shen, L; Zhao, Y; Zhang, J; Zhou, J; Wang, X; Liu, Q 
In Press 
Yes 
Archives of Toxicology
ISSN: 0340-5761
EISSN: 1432-0738 
87 
991-1000 
English 
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. 
Arsenite; Epithelial-mesenchymal transition; Cancer stem cell-like properties; Nuclear factor kappa B; Snail; Neoplastic transformation 
IRIS
• Arsenic Hazard ID
     1. Initial Lit Search
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     2. Lit Search Updates through Oct 2015
          PubMed
          WOS
          ToxNet
          Considered
     4. Considered through Oct 2015
     5. Additions through Oct 2015
     6. Cluster Filter through Oct 2015
     7. Other Studies through Oct 2015
          MOA
          iAs MOA Literature Categorization
               Immune
               Oxidative Stress
• Arsenic (Inorganic)
     1. Literature
          PubMed
          Lit search updates through Oct 2015
     3. Hazard ID Screening
          Other potentially supporting studies
     4. Adverse Outcome Pathways/Networks Screening
          Relevant
• Arsenic MOA
     4. Adverse Outcome Pathways
          Cellular differentiation and malignant transformation
     5. Health Effect
          Skin Diseases
          Cancer
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          Health Effect Screening
          MOA Cluster