A link between the fibroblast growth factor axis and the miR-16 family reveals potential new treatment combinations in mesothelioma

Mol Oncol. 2018 Jan;12(1):58-73. doi: 10.1002/1878-0261.12150. Epub 2017 Nov 18.


Malignant pleural mesothelioma (MPM) is an aggressive malignancy with very limited therapeutic options. Fibroblast growth factor (FGF) signals play important roles in mesothelioma cell growth. Several FGFs and FGF receptors (FGFRs) are predicted targets of the miR-15/16 family, which is downregulated in MPM. The aim of this study was to explore the link between the miR-15/16 family and the FGF axis in MPM. Expression analyses via RT-qPCR showed downregulation of the FGF axis after transfection with miR-15/16 mimics. Direct interaction was confirmed by luciferase reporter assays. Restoration of miR-15/16 led to dose-dependent growth inhibition in MPM cell lines, which significantly correlated with their sensitivity to FGFR inhibition. Treatment with recombinant FGF2 prevented growth inhibition and further reduced the levels of FGF/R-targeting microRNAs, indicating a vicious cycle between miR-15/16 down- and FGF/FGFR signaling upregulation. Combined inhibition of two independent miR-15/16 targets, the FGF axis and Bcl-2, resulted in additive or synergistic activity. Our data indicate that post-transcriptional repression of FGF-mediated signals contributes to the tumor suppressor function of the microRNA-15/16 family. Inhibiting hyperactivated FGF signals and Bcl-2 might serve as a novel therapeutic combination strategy in MPM.

Keywords: fibroblast growth factor, fibroblast growth factor receptor; malignant pleural mesothelioma; microRNA-15; microRNA-16.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Down-Regulation
  • Fibroblast Growth Factor 2 / therapeutic use*
  • Fibroblast Growth Factors / metabolism*
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / metabolism*
  • Mesothelioma / drug therapy*
  • Mesothelioma / metabolism*
  • Mesothelioma, Malignant
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Pleura / pathology
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Receptors, Fibroblast Growth Factor / genetics
  • Receptors, Fibroblast Growth Factor / metabolism
  • Recombinant Proteins / therapeutic use*
  • Up-Regulation


  • MIRN15 microRNA, human
  • MIRN16 microRNA, human
  • MicroRNAs
  • Proto-Oncogene Proteins c-bcl-2
  • Receptors, Fibroblast Growth Factor
  • Recombinant Proteins
  • Fibroblast Growth Factor 2
  • Fibroblast Growth Factors