Background: Arsenic is one of the most common environmental contaminants. Long-term exposure to arsenic causes human bronchial epithelial cell (HBEC) malignant transformation and lung cancer. However, the mechanism of arsenic lung carcinogenesis is not clear, and the migratory and invasive properties of arsenic-transformed cells (As-transformed cells) have rarely been studied.
Objectives: This study was designed to investigate the migratory and invasive behavior of As-transformed HBECs and the underlying mechanism.
Methods: As-transformed p53lowHBECs were generated by exposing p53-knockdown HBECs to sodium arsenite (2.5 μM) for 16 weeks. Cell migration was assessed by transwell migration and wound-healing assay. Cell invasion was evaluated using Matrigel-coated transwell chambers. Gene overexpression, small interfering RNA (siRNA) knockdowns, and pharmacological inhibitors were used to determine the potential mechanism responsible for enhanced cell migration and invasion.
Results: Transwell migration and invasion assays revealed that As-transformed p53lowHBECs were highly migratory and invasive. Akt (also known as protein kinase B) and extracellular signal-regulated protein kinase 1/2 (Erk1/2) were strongly activated in As-transformed p53lowHBECs. Stable expression of microRNA 200b in As-transformed p53lowHBECs abolished Akt and Erk1/2 activation and completely suppressed cell migration and invasion. Pharmacological inactivation of Akt but not Erk1/2 significantly decreased cell migration and invasion. Inhibition of Akt reduced the expression of epithelial-to-mesenchymal transition-inducing transcription factors zinc-finger E-box-binding homeobox factor 1 (ZEB1) and ZEB2. siRNA knockdown of ZEB1 and ZEB2 impaired As-transformed p53lowHBEC migration and invasion.
Conclusions: Akt activation plays a critical role in enabling As-transformed HBEC migration and invasion by promoting ZEB1 and ZEB2 expression.
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| http://dx.doi.org/10.1289/ehp.1104061 | DOI Listing |
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