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.
Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 210029, Jiangsu, People's Republic of China.
Rongrong
R
Jiang
Yuan
Y
Li
Yuan
Y
Xu
Yun
Y
Zhou
Ying
Y
Pang
Lu
L
Shen
Yue
Y
Zhao
Jianping
J
Zhang
Jianwei
J
Zhou
Xinru
X
Wang
Qizhan
Q
Liu
D018053:Arsenites / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D020672:I-kappa B Proteins / Q000378:metabolism*; D015603:Keratinocytes / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D000072000:NF-KappaB Inhibitor alpha; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D010641:Phenotype; D015398:Signal Transduction / Q000187:drug effects; D000071250:Snail Family Transcription Factors; D017670:Sodium Compounds / Q000633:toxicity*; D013997:Time Factors; D051996:Transcription Factor RelA / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
D018053:Arsenites; D002273:Carcinogens; D020672:I-kappa B Proteins; C000606204:NFKBIA protein, human; C498143:RELA protein, human; D000071250:Snail Family Transcription Factors; D017670:Sodium Compounds; D051996:Transcription Factor RelA; D014157:Transcription Factors; D000072000:NF-KappaB Inhibitor alpha; C017947:sodium arsenite; D051550:I-kappa B Kinase; C496560:IKBKB protein, human