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

Our plain-English summary of A link between the fibroblast growth factor axis and the miR-16 family reveals potential new treatment combinations in mesothelioma, by K. Schelch, M.B. Kirschner, M. Williams, et al (Molecular Oncology, 2018).

The study

• Authors: K. Schelch, M.B. Kirschner, M. Williams, Y.Y. Cheng, N. van Zandwijk, M. Grusch, G. Reid
• Journal: Molecular Oncology
• Published: 2018;12(1):58-73
• Cited by: 30 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

© 2017 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

In plain English

This was a laboratory study of malignant pleural mesothelioma cells grown in the lab. No patients were studied, and asbestos exposure was not examined. The authors looked at a family of small regulatory molecules called miR-15/16 and at growth-signal proteins called FGFs and their receptors (FGFRs). They tested 7 mesothelioma cell lines plus 5 drug-resistant versions. Compared with a non-cancerous mesothelial cell line, MeT-5A, these cells had higher FGFR1, FGF2 and FGF18 and lower miR-15a, miR-15b and miR-16. Adding these microRNAs back lowered the expression of several FGF and FGFR genes and slowed cell growth in a dose-dependent way, most strongly in three cell lines. Cell lines that responded more to the microRNAs also responded more to an FGFR1-blocking drug. Adding FGF2 further lowered the microRNAs in most cell lines, which the authors described as a possible vicious cycle. A drug blocking Bcl-2 (another target of these microRNAs) combined with an FGFR-blocking drug was synergistic in all three cell lines tested. The authors concluded this combination deserves further consideration as a mesothelioma treatment strategy.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) study using human mesothelioma cell lines
• Who was studied: 7 malignant pleural mesothelioma (MPM) cell lines plus 5 drug-resistant derivatives, with the non-malignant mesothelial cell line MeT-5A as reference (LP9 also used as a control mesothelial line); study place and dates of experiments not stated beyond author affiliations (Sydney, Vienna, Zurich)
• Exposure: No asbestos exposure was studied. Cells were treated with miR-15a, miR-15b and miR-16 mimics, recombinant FGF2, the FGFR1 inhibitor PD166866, the multikinase inhibitor ponatinib, and the Bcl-2 inhibitors venetoclax and obatoclax
• Main results:
  • Compared with MeT-5A, the MPM cell lines showed overexpression of FGFR1, FGF2 and FGF18 and reduced expression of miR-15a, miR-15b and miR-16
  • All three microRNA mimics lowered FGFR1 and FGFR4 expression. FGF1, FGF2 and FGF18 were also reduced, and FGF5 was not. Luciferase assays confirmed direct interaction with the predicted target sites.
  • MicroRNA mimics caused dose-dependent growth repression of MPM cells, strongest in the MSTO, SPC212 and P31 cell lines
  • Across cell lines, growth repression by the mimics correlated significantly (Pearson) with sensitivity to the FGFR1 inhibitor PD166866; no correlation coefficient is given in the text
  • FGF2 added 24 hours after transfection reduced or prevented mimic-induced growth inhibition; added at 96 hours it had no effect on cell growth
  • Stimulation with FGF2 for 24 hours further lowered miR-15/16 levels in the majority of cell lines, which the authors interpreted as a possible vicious cycle
  • In the three sensitive cell lines, the FGFR inhibitors PD166866 and ponatinib raised miR-15a, miR-15b and miR-16 levels
  • Combining mimics with PD166866 gave weaker effects than the single treatments at higher mimic doses, which the authors read as target competition
  • The obatoclax plus ponatinib combination was synergistic in all three cell lines tested, with combination indices below 1, especially at lower concentrations
• The authors' conclusion: The authors concluded that combined inhibition of FGFR1 and Bcl-2, two miR-15/16 targets, had synergistic effects on tumor cell growth and deserves further consideration as a combination strategy in MPM
• Limitations the authors state:
  • The authors note that baseline FGF/FGFR levels did not correlate significantly with miR-15/16 expression, so these microRNAs contribute to, but do not fully control, FGF/FGFR expression
  • The authors note that baseline FGF/FGFR or miR-15/16 levels did not predict which MPM cell lines responded to FGFR inhibition or mimics

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Fibroblast, Mesothelioma, Pleural Mesothelioma.

Related studies

• Restoring expression of miR-16: a novel approach to therapy for malignant pleural mesothelioma — G. Reid, M.E. Pel, et al. (2013)
• Fibroblast growth factor-10 prevents asbestos-induced alveolar epithelial cell apoptosis by a mitogen-activated protein kinase-dependent mechanism — D. Upadhyay, V. Panduri, et al. (2005)
• Pulmonary reaction to long and short asbestos fibers is independent of fibroblast growth factor production by alveolar macrophages — I.Y. Adamson, D.H. Bowden (1990)
• Carborundum pneumoconiosis. Fibers in the mineral activate macrophages to produce fibroblast growth factors and sustain the chronic inflammatory disease — R. Bégin, A. Dufresne, et al. (1989)
• FGF2 and EGF induce epithelial-mesenchymal transition in malignant pleural mesothelioma cells via a MAPKinase/MMP1 signal — K. Schelch, C. Wagner, et al. (2018)
• Treatment of bronchial fistula after extraplural pneumonectomy using flexible bronchoscopy with the administration of OK432, fibroblast growth factor basic and fibrin glue sealant — N. Kondo, M. Hashimoto, et al. (2020)

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