title: Akt activation is responsible for enhanced migratory and invasive behavior of arsenic-transformed human bronchial epithelial cells.
abstract: 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.
  
  
  OBJECTIVE
  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.
authors.affiliation: Department of Physiology, Michigan State University, East Lansing, MI 48824, USA.
authors.forename: Zhishan
authors.initials: Z
authors.lastname: Wang
authors.forename: Junling
authors.initials: J
authors.lastname: Yang
authors.forename: Theresa
authors.initials: T
authors.lastname: Fisher
authors.forename: Hua
authors.initials: H
authors.lastname: Xiao
authors.forename: Yiguo
authors.initials: Y
authors.lastname: Jiang
authors.forename: Chengfeng
authors.initials: C
authors.lastname: Yang
mesh_terms: D001151:Arsenic / Q000633:toxicity*; D001980:Bronchi / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced*; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009361:Neoplasm Invasiveness / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D020545:Respiratory Mucosa / Q000187:drug effects*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D000074165:Zinc Finger E-box Binding Homeobox 2; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D018398:Homeodomain Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; C486307:ZEB1 protein, human; C492363:ZEB2 protein, human; D000074165:Zinc Finger E-box Binding Homeobox 2; D000071799:Zinc Finger E-box-Binding Homeobox 1; D051057:Proto-Oncogene Proteins c-akt; D001151:Arsenic