Fas signaling promotes motility and metastasis through epithelial-mesenchymal transition in gastrointestinal cancer

Oncogene. 2013 Feb 28;32(9):1183-92. doi: 10.1038/onc.2012.126. Epub 2012 Apr 16.

Abstract

Fas signaling was reported to participate in cell apoptosis. However, this pathway has also been shown to promote tumor cell motility, leading to the hypothesis that Fas signaling may induce epithelial-mesenchymal transition (EMT) to promote metastasis. The effects of Fas-ligand (FasL) treatment and inhibition of Fas signaling on colorectal and gastric cancer cells were tested using motility assay, immunofluorescence, RT-PCR and immunoblot analyses. Fas signaling downregulated epithelial markers, upregulated mesenchymal markers and promoted motility in gastrointestinal (GI) cancer cells. FasL treatment also increased the expression of EMT transcriptional factors in the nucleus and induced a spindle shape cell morphology in these cells. Knockdown of Snail or Twist expression significantly decreased FasL-induced motility. The ERK1/2 pathway was activated by Fas signaling and is required for FasL-induced EMT and motility. Moreover, oxaliplatin, a chemotherapeutic agent, induced EMT partly through Fas signaling. Evaluation of human GI clinical specimens showed that FasL expression increased whereas E-cadherin expression decreased during GI cancer progression. Both markers were significantly inversely correlated. Tissue samples with a non-EMT phenotype were mainly distributed in patients with early cancer stages, whereas samples with an EMT phenotype were mostly distributed in patients with advanced cancer stages. A non-EMT phenotype significantly correlated with better prognosis. Altogether, these data indicate that Fas signaling may induce EMT to promote tumor motility and metastasis in GI cancer in vivo and in vitro.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cadherins / metabolism
  • Cell Line, Tumor
  • Cell Movement*
  • Epithelial-Mesenchymal Transition*
  • Fas Ligand Protein / pharmacology
  • Gastrointestinal Neoplasms / metabolism*
  • Gastrointestinal Neoplasms / pathology*
  • Humans
  • Organoplatinum Compounds / pharmacology
  • Oxaliplatin
  • Prognosis
  • Signal Transduction
  • fas Receptor / metabolism*

Substances

  • Cadherins
  • FAS protein, human
  • Fas Ligand Protein
  • Organoplatinum Compounds
  • fas Receptor
  • Oxaliplatin