A link between the fibroblast growth factor axis and the miR‐16 family reveals potential new treatment combinations in mesothelioma. Issue 1 (18th November 2017)

• Record Type: Journal Article
• Authors: Schelch, Karin; Kirschner, Michaela B.; Williams, Marissa; Cheng, Yuen Y.; van Zandwijk, Nico; Grusch, Michael; Reid, Glen
• Is Part Of: Molecular oncology. Volume 12:Issue 1(2018)
• Page Start: 58
• Page End: 73
• Publication Date: 2017-11-18
• Subjects: fibroblast growth factor, fibroblast growth factor receptor -- malignant pleural mesothelioma -- microRNA‐15 -- microRNA‐16; Cancer -- Molecular aspects -- Periodicals; 616.994005
• DOI: 10.1002/1878-0261.12150
• Languages: English
• ISSNs: 1574-7891

Abstract

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. Abstract : Loss of miR‐15/16 plays a role in the overexpression of the FGF axis in MPM. We identified a vicious cycle of malignant growth between FGF signals and miR‐15/16 and show that cells which are more sensitive to FGFR inhibition also respond better to microRNA mimics, providing evidence for microRNA replacement as an alternative therapeutic approach to FGF/R inhibition in MPM.