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

Karin Schelch,Nico Van Zandwijk,Marissa Williams,Glen Reid,Michaela B Kirschner,Michael Grusch,Yuen Y Cheng

doi:10.1002/1878-0261.12150

Abstract

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.

Highlights

Malignant pleural mesothelioma (MPM) is a very aggressive malignancy of the pleural linings with dismal outcome and limited, mostly palliative therapeutic options
Downregulation of the microRNA-15/16 family corresponds with an upregulation of the Fibroblast growth factor (FGF) axis in MPM cell lines
To investigate the relationship between the miR-15/ 16 family and the FGF axis, we first measured the expression of miR-15a, miR-15b, and miR-16 as well as several members of the FGF/fibroblast growth factor receptor (FGFR) family in a panel of seven MPM cell lines via RT-qPCR

Summary

Introduction

Malignant pleural mesothelioma (MPM) is a very aggressive malignancy of the pleural linings with dismal outcome (median survival of 9–17 months) and limited, mostly palliative therapeutic options (van Zandwijk et al, 2013). As classical malignant drivers such as mutated EGFR or Raf are uncommon in MPM, treatments targeting these mutations are ineffective in this disease (Dubey et al, 2010; Garland et al, 2007; Govindan et al, 2005). Genomic analysis has revealed genetic deletions in MPM largely in genes considered to be tumor suppressive, such as P16/ CDKN2A and NF2 (Jaurand and Fleury-Feith, 2005), which are not targetable. We and others have previously identified fibroblast growth factors (FGFs) and their receptors (FGFRs) as signaling molecules. Abbreviations FGF, fibroblast growth factor; FGFR, fibroblast growth factor receptor; MPM, malignant pleural mesothelioma.

Objectives

Methods

Results

Conclusion