Expression of the FGFR2 mesenchymal splicing variant in epithelial cells drives epithelial-mesenchymal transition

Oncotarget. 2016 Feb 2;7(5):5440-60. doi: 10.18632/oncotarget.6706.

Abstract

The FGFRs are receptor tyrosine kinases expressed by tissue-specific alternative splicing in epithelial IIIb or mesenchymal IIIc isoforms. Deregulation of FGF/FGFR signaling unbalances the epithelial-stromal homeostasis and may lead to cancer development. In the epithelial-context, while FGFR2b/KGFR acts as tumor suppressor, FGFR2c appears to play an oncogenic role. Based on our recent observation that the switching of FGFR2b versus FGFR2c induces EMT, here we investigated the biological outcome of the ectopic expression of FGFR2c in normal human keratinocytes. Morphological analysis showed that, differently from FGFR2b overexpression, the forced expression and activation of FGFR2c drive the epithelial cells to acquire a mesenchymal-like shape and actin reorganization. Moreover, the appearance of invasiveness and anchorage-independent growth ability in FGFR2c transfected keratinocytes was consistent with the potential tumorigenic role proposed for this receptor variant. Biochemical and molecular approaches revealed that the observed phenotypic changes were accompanied by modulation of EMT biomarkers and indicated the involvement of EMT transcription factors and miRs. Finally, the analysis of the expression pattern of discriminating markers strongly suggested that activation of FGFR2c triggers a process corresponding to the initiation of the pathological type III EMT, but not to the more physiological type II EMT occurring during FGFR2b-mediated wound healing.

Keywords: FGFR2; epithelial-mesenchymal transition; human keratinocytes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing*
  • Apoptosis
  • Blotting, Western
  • Cell Adhesion
  • Cell Movement*
  • Cell Proliferation
  • Cells, Cultured
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology*
  • Epithelial-Mesenchymal Transition*
  • Fluorescent Antibody Technique
  • Humans
  • Immunoenzyme Techniques
  • Keratinocytes / metabolism
  • Keratinocytes / pathology*
  • Phosphorylation
  • Protein Isoforms
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Receptor, Fibroblast Growth Factor, Type 2 / genetics
  • Receptor, Fibroblast Growth Factor, Type 2 / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Wound Healing

Substances

  • Protein Isoforms
  • RNA, Messenger
  • Receptor, Fibroblast Growth Factor, Type 2