The FGFR4-388arg Variant Promotes Lung Cancer Progression by N-Cadherin Induction

Sci Rep. 2018 Feb 5;8(1):2394. doi: 10.1038/s41598-018-20570-3.

Abstract

The FGFR4-388Arg variant has been related to poor prognosis in several types of cancer, including lung cancer. The mechanism underlying this association has not been addressed in detail in patients with this pathology. Here, we report that this FGFR4 variant induces MAPK and STAT3 activation and causes pro-oncogenic effects in NSCLC in vitro and in vivo. This variant induces the expression of EMT-related genes, such as N-cadherin, vimentin, Snail1 and Twist1. Indeed, the induction of N-cadherin protein expression by this variant is essential for its pro-tumorigenic role. The presence of the FGFR4-388Arg variant correlates with higher N-cadherin expression levels in clinical NSCLC samples and with poorer outcome in patients with FGFR expression. These results support the prognostic role of this FGFR variant in lung cancer and show that these effects may be mediated by the induction of N-cadherin expression and an EMT phenotype.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / genetics*
  • Antigens, CD / metabolism
  • Cadherins / genetics*
  • Cadherins / metabolism
  • Carcinoma, Non-Small-Cell Lung / diagnosis
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / mortality
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Line, Tumor
  • Disease Progression
  • Epithelial-Mesenchymal Transition / genetics
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Heterografts
  • Humans
  • Lung Neoplasms / diagnosis
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / mortality
  • Lung Neoplasms / pathology
  • Male
  • Mice
  • Mice, Nude
  • Mitogen-Activated Protein Kinases / genetics
  • Mitogen-Activated Protein Kinases / metabolism
  • Mutation*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Prognosis
  • Receptor, Fibroblast Growth Factor, Type 4 / genetics*
  • Receptor, Fibroblast Growth Factor, Type 4 / metabolism
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism
  • Snail Family Transcription Factors / genetics
  • Snail Family Transcription Factors / metabolism
  • Survival Analysis
  • Twist-Related Protein 1 / genetics
  • Twist-Related Protein 1 / metabolism
  • Vimentin / genetics
  • Vimentin / metabolism

Substances

  • Antigens, CD
  • CDH2 protein, human
  • Cadherins
  • Nuclear Proteins
  • SNAI1 protein, human
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Snail Family Transcription Factors
  • TWIST1 protein, human
  • Twist-Related Protein 1
  • Vimentin
  • FGFR4 protein, human
  • Receptor, Fibroblast Growth Factor, Type 4
  • Mitogen-Activated Protein Kinases