Abstract
BackgroundArsenic 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.MethodsTo 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.ResultsWith 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.ConclusionsEMT, regulated by HIF-2α, and the development of a cancer stem cell-like phenotype are associated with arsenite-induced transformation of HBE cells.
Highlights
The epithelial-mesenchymal transition (EMT) is a developmental process by which epithelial cells are converted to mesenchymal cells during embryogenesis [1]
Chronic arsenite exposure causes EMT of human bronchial epithelial (HBE) cells A low concentration (1.0 mM) of arsenite increased the neoplastic transformation of HBE cells, as determined by anchorage-independent growth in soft agar and tumorigenesis in nude mice (Figure S1)
This change indicates that chronic arsenite exposure causes EMT of HBE cells
Summary
The epithelial-mesenchymal transition (EMT) is a developmental process by which epithelial cells are converted to mesenchymal cells during embryogenesis [1]. CSCs, which constitute a small portion of neoplastic cells, are defined by their capacity to produce new tumors. For this reason, they have been termed ‘tumorinitiating cells’ [5]. 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
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