A link between the fibroblast growth factor axis and the miR‐16 family reveals potential new treatment combinations in mesothelioma
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 downregulate...
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Format: | Article |
Language: | English |
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Wiley
2018-01-01
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Series: | Molecular Oncology |
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Online Access: | https://doi.org/10.1002/1878-0261.12150 |
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author | Karin Schelch Michaela B. Kirschner Marissa Williams Yuen Y. Cheng Nico vanZandwijk Michael Grusch Glen Reid |
author_facet | Karin Schelch Michaela B. Kirschner Marissa Williams Yuen Y. Cheng Nico vanZandwijk Michael Grusch Glen Reid |
author_sort | Karin Schelch |
collection | DOAJ |
description | 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. |
first_indexed | 2024-04-12T22:04:11Z |
format | Article |
id | doaj.art-b094d40bad314cdfb3c62ed871bcdebd |
institution | Directory Open Access Journal |
issn | 1574-7891 1878-0261 |
language | English |
last_indexed | 2024-04-12T22:04:11Z |
publishDate | 2018-01-01 |
publisher | Wiley |
record_format | Article |
series | Molecular Oncology |
spelling | doaj.art-b094d40bad314cdfb3c62ed871bcdebd2022-12-22T03:15:01ZengWileyMolecular Oncology1574-78911878-02612018-01-01121587310.1002/1878-0261.12150A link between the fibroblast growth factor axis and the miR‐16 family reveals potential new treatment combinations in mesotheliomaKarin Schelch0Michaela B. Kirschner1Marissa Williams2Yuen Y. Cheng3Nico vanZandwijk4Michael Grusch5Glen Reid6Asbestos Diseases Research Institute Sydney AustraliaAsbestos Diseases Research Institute Sydney AustraliaAsbestos Diseases Research Institute Sydney AustraliaAsbestos Diseases Research Institute Sydney AustraliaAsbestos Diseases Research Institute Sydney AustraliaDepartment of Medicine I Institute of Cancer Research Medical University of Vienna AustriaAsbestos Diseases Research Institute Sydney AustraliaMalignant 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.https://doi.org/10.1002/1878-0261.12150fibroblast growth factor, fibroblast growth factor receptormalignant pleural mesotheliomamicroRNA‐15microRNA‐16 |
spellingShingle | Karin Schelch Michaela B. Kirschner Marissa Williams Yuen Y. Cheng Nico vanZandwijk Michael Grusch Glen Reid A link between the fibroblast growth factor axis and the miR‐16 family reveals potential new treatment combinations in mesothelioma Molecular Oncology fibroblast growth factor, fibroblast growth factor receptor malignant pleural mesothelioma microRNA‐15 microRNA‐16 |
title | A link between the fibroblast growth factor axis and the miR‐16 family reveals potential new treatment combinations in mesothelioma |
title_full | A link between the fibroblast growth factor axis and the miR‐16 family reveals potential new treatment combinations in mesothelioma |
title_fullStr | A link between the fibroblast growth factor axis and the miR‐16 family reveals potential new treatment combinations in mesothelioma |
title_full_unstemmed | A link between the fibroblast growth factor axis and the miR‐16 family reveals potential new treatment combinations in mesothelioma |
title_short | A link between the fibroblast growth factor axis and the miR‐16 family reveals potential new treatment combinations in mesothelioma |
title_sort | link between the fibroblast growth factor axis and the mir 16 family reveals potential new treatment combinations in mesothelioma |
topic | fibroblast growth factor, fibroblast growth factor receptor malignant pleural mesothelioma microRNA‐15 microRNA‐16 |
url | https://doi.org/10.1002/1878-0261.12150 |
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