Hypoxia activated EGFR signaling induces epithelial to mesenchymal transition (EMT)

PLoS One. 2012;7(11):e49766. doi: 10.1371/journal.pone.0049766. Epub 2012 Nov 21.


Metastasis is a multi-step process which requires the conversion of polarized epithelial cells to mesenchymal cells, Epithelial-Mesenchymal Transition (EMT). EMT is essential during embryonic morphogenesis and has been implicated in the progression of primary tumors towards metastasis. Hypoxia is known to induce EMT; however the molecular mechanism is still poorly understood. Using the A431 epithelial cancer cell line, we show that cells grown under hypoxic conditions migrated faster than cells grown under normal oxygen environment. Cells grown under hypoxia showed reduced adhesion to the extracellular matrix (ECM) probably due to reduced number of Vinculin patches. Growth under hypoxic conditions also led to down regulation of E-cadherin and up regulation of vimentin expression. The increased motility of cells grown under hypoxia could be due to redistribution of Rac1 to the plasma membrane as opposed to increased expression of Rac1. EGF (Epidermal Growth Factor) is a known inducer of EMT and growth of A431 cells in the absence of oxygen led to increased expression of EGFR (EGF Receptor). Treatment of A431 cells with EGF led to reduced cell adhesion to ECM, increased cell motility and other EMT characteristics. Furthermore, this transition was blocked by the monoclonal antibody Cetuximab. Cetuximab also blocked the hypoxia-induced EMT suggesting that cell growth under hypoxic conditions led to activation of EGFR signaling and induction of EMT phenotype.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal, Humanized / administration & dosage
  • Cadherins / metabolism
  • Cell Adhesion / drug effects
  • Cell Hypoxia* / drug effects
  • Cell Hypoxia* / physiology
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cetuximab
  • Epithelial Cells* / drug effects
  • Epithelial Cells* / metabolism
  • Epithelial-Mesenchymal Transition* / drug effects
  • Epithelial-Mesenchymal Transition* / physiology
  • ErbB Receptors* / metabolism
  • ErbB Receptors* / pharmacology
  • Extracellular Matrix / drug effects
  • Extracellular Matrix / metabolism
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Signal Transduction*
  • Vimentin / metabolism
  • Vinculin / metabolism
  • rac1 GTP-Binding Protein / metabolism


  • Antibodies, Monoclonal, Humanized
  • Cadherins
  • RAC1 protein, human
  • Vimentin
  • Vinculin
  • EGFR protein, human
  • ErbB Receptors
  • rac1 GTP-Binding Protein
  • Cetuximab

Grant support

This work was partially supported by grants from the ARC tier 1 grant (RG28/05 & RG52/10 to TT), the Ministry of Education (ARC: T206B3211 to SKS), and the Agency for Science, Technology and Research (BMRC: 08/1/22/19/575 to SKS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.