EMT and stem cell-like properties associated with HIF-2α are involved in arsenite-induced transformation of human bronchial epithelial cells.
BACKGROUND
Arsenic is well-established as a human carcinogen, but the molecular mechanisms leading to arsenic-induced carcinogenesis are complex and elusive. It is not been determined if the epithelial-mesenchymal transition (EMT) and stem cell-like properties contribute in causing to carcinogen-induced malignant transformation and subsequent tumor formation.


METHODS
To investigate the molecular mechanisms underlying EMT and the emergence of cancer stem cell-like properties during neoplastic transformation of human bronchial epithelial (HBE) cells induced by chronic exposure to arsenite. HBE cells were continuously exposed to arsenite. Spheroid formation assays and analyses of side populations (SPs) were performed to confirm that arsenite induces the acquired EMT and cancer stem cell-like phenotype. Treated HBE cells were molecularly characterized by RT-PCR, Western blots, immunofluorescence, Southwestern assays, reporter assays, and chromatin immunoprecipitation.


RESULTS
With chronic exposure to arsenite, HBE cells undergo an EMT and then acquire a malignant cancer stem cell-like phenotype. Twist1 and Bmi1 are involved in arsenite-induced EMT. The process is directly regulated by HIF-2α. The self-renewal genes, Oct4, Bmi1, and ALDH1, are necessary for arsenite-mediated maintenance of stem cells.


CONCLUSIONS
EMT, regulated by HIF-2α, and the development of a cancer stem cell-like phenotype are associated with arsenite-induced transformation of HBE cells.
Institute of Toxicology, Nanjing Medical University, Nanjing, People's Republic of China.
Yuan
Y
Xu
Yuan
Y
Li
Ying
Y
Pang
Min
M
Ling
Lu
L
Shen
Xiaojun
X
Yang
Jianping
J
Zhang
Jianwei
J
Zhou
Xinru
X
Wang
Qizhan
Q
Liu
D018053:Arsenites / Q000494:pharmacology*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D001980:Bronchi / Q000187:drug effects / Q000378:metabolism*; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D063150:Polycomb Repressive Complex 1 / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism*; D013723:Teratogens / Q000494:pharmacology; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
D018053:Arsenites; D051792:Basic Helix-Loop-Helix Proteins; D009687:Nuclear Proteins; D063150:Polycomb Repressive Complex 1; D013723:Teratogens; D051879:Twist-Related Protein 1; D000099162:Endothelial PAS Domain-Containing Protein 1; C069077:BMI1 protein, human; C103173:TWIST1 protein, human; C015001:arsenite