Online citations, reference lists, and bibliographies.
← Back to Search

A Link Between The Fibroblast Growth Factor Axis And The MiR‐16 Family Reveals Potential New Treatment Combinations In Mesothelioma

K. Schelch, M. Kirschner, M. Williams, Y. Cheng, N. van Zandwijk, M. Grusch, G. Reid
Published 2018 · Biology, Medicine

Cite This
Download PDF
Analyze on Scholarcy
Share
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.
This paper references
hsa - miR - 29 c * is linked to the prognosis of malignant pleuralmesothelioma
HI Pass (2010)
10.1016/j.critrevonc.2012.03.001
The ticking time-bomb of asbestos: its insidious role in the development of malignant mesothelioma.
Anthony Linton (2012)
10.18632/oncotarget.9515
Inhibition of FGF/FGFR autocrine signaling in mesothelioma with the FGF ligand trap, FP-1039/GSK3052230
C. Blackwell (2016)
10.1097/JTO.0b013e3182a0840a
ZIC1 Is Silenced and Has Tumor Suppressor Function in Malignant Pleural Mesothelioma
Y. Cheng (2013)
10.18632/oncotarget.6504
miR-16 targets fibroblast growth factor 2 to inhibit NPC cell proliferation and invasion via PI3K/AKT and MAPK signaling pathways
Qingmei He (2016)
A neutralizing antifibroblast growth factor (FGF) 8 monoclonal antibody shows anti-tumor activity against FGF8b-expressing
K Maruyama-Takahashi (2008)
10.1111/j.1440-1843.2005.00694.x
Pathogenesis of malignant pleural mesothelioma
M. Jaurand (2005)
10.1038/nm.1880
The miR-15a–miR-16-1 cluster controls prostate cancer by targeting multiple oncogenic activities
D. Bonci (2008)
A neutralizing antifibroblast growth factor (FGF) 8 monoclonal antibody shows anti-tumor activity against FGF8b-expressing LNCaP xenografts in androgen-dependent andindependent conditions
K Maruyama-Takahashi (2008)
Bevacizumab 15 mg / kg plus cisplatin - pemetrexed ( CP ) triplet versus CP doublet in malignant pleural mesothelioma ( MPM ) : results of the IFCT - GFPC - 0701 MAPS randomized phase 3 trial
G Zalcman (2015)
tumor activity against FGF8b-expressing LNCaP xenografts in androgen-dependent and -independent conditions. Prostate
T. Metzner (2011)
10.2174/156800909789057006
The role of fibroblast growth factors in tumor growth.
M. Korc (2009)
10.1186/s40064-016-3310-2
BCL-2 inhibition impairs mitochondrial function and targets oral tongue squamous cell carcinoma
L. Xiong (2016)
10.1038/jid.2011.177
Fibroblast growth factor receptors as therapeutic targets in human melanoma: synergism with BRAF inhibition.
T. Metzner (2011)
Synergistic anti-leukemic interactions between ABT-199 and panobinostat in acute myeloid leukemia ex vivo.
Jonathan I. Schwartz (2016)
A (2017) The inhibition of FGF receptor 1 activity mediates sorafenib antiproliferative effects in human malignant pleural mesothelioma tumor-initiating cells
A Pattarozzi (2017)
10.1097/PPO.0000000000000242
Novel Targeted Therapies for Metastatic Melanoma
W. Iams (2017)
10.1093/annonc/mdt412
Restoring expression of miR-16: a novel approach to therapy for malignant pleural mesothelioma.
G. Reid (2013)
10.1186/gb-2001-2-3-reviews3005
Fibroblast growth factors
D. Ornitz (2001)
29c* is linked to the prognosis of malignant pleural mesothelioma
A. Pattarozzi (2017)
10.1200/JCO.2006.09.7634
Phase II study of erlotinib in patients with malignant pleural mesothelioma: a Southwest Oncology Group Study.
L. Garland (2007)
10.1038/nrg1415
MicroRNAs: small RNAs with a big role in gene regulation
L. He (2004)
10.1126/scitranslmed.3001451
Frequent and Focal FGFR1 Amplification Associates with Therapeutically Tractable FGFR1 Dependency in Squamous Cell Lung Cancer
J. Weiss (2010)
10.7554/eLife.05005
Predicting effective microRNA target sites in mammalian mRNAs
V. Agarwal (2015)
10.3978/j.issn.2225-319X.2012.11.04
Malignant pleural mesothelioma: an epidemiological perspective.
Benjamin M. Robinson (2012)
10.1002/med.21288
FGF Receptors: Cancer Biology and Therapeutics
M. Katoh (2014)
10.1016/j.biopha.2013.12.001
miR-99a promotes proliferation targeting FGFR3 in human epithelial ovarian cancer cells.
Haiyang Jiang (2014)
A small molecule panBcl-2 family inhibitor, GX15-070, induces apoptosis and enhances cisplatin-induced apoptosis in non-small cell lung cancer cells
J Li (2008)
10.1158/1078-0432.CCR-13-3060
FGFR1 mRNA and Protein Expression, not Gene Copy Number, Predict FGFR TKI Sensitivity across All Lung Cancer Histologies
M. Wynes (2014)
10.1038/bjc.2016.331
Co-targeting of FAK and MDM2 triggers additive anti-proliferative effects in mesothelioma via a coordinated reactivation of p53
Wen-bin Ou (2016)
10.3389/fgene.2012.00120
miR-34 – a microRNA replacement therapy is headed to the clinic
A. Bader (2012)
10.1158/1078-0432.CCR-04-1940
Gefitinib in Patients with Malignant Mesothelioma: A Phase II Study by the Cancer and Leukemia Group B
R. Govindan (2005)
10.1097/JTO.0b013e31820db125
MicroRNAs Dysregulation in Human Malignant Pleural Mesothelioma
Veronica Balatti (2011)
10.1007/s11864-001-0033-5
Metastatic melanoma
W. Sun (2001)
MiR15a and MiR-16 control Bmi-1 expression in ovarian cancer
R Bhattacharya (2009)
Small Molecule Therapeutics The Fibroblast Growth Factor Receptor Genetic Status as a Potential Predictor of the Sensitivity to CH 5183284 / Debio 1347 , a Novel Selective FGFR Inhibitor
Y. Nakanishi (2014)
10.6004/JNCCN.2012.0006
[Malignant pleural mesothelioma].
Q. Kong (1983)
10.1146/annurev.med.59.053006.104707
MicroRNAs in Cancer.
R. Garzon (2009)
10.1042/BST0381571
Post-transcriptional and post-translational regulation of Bcl2.
S. Willimott (2010)
10.3978/j.issn.2072-1439.2013.11.28
Guidelines for the diagnosis and treatment of malignant pleural mesothelioma.
N. van Zandwijk (2013)
10.1164/rccm.201503-0461LE
A Significant Metabolic and Radiological Response after a Novel Targeted MicroRNA-based Treatment Approach in Malignant Pleural Mesothelioma.
S. Kao (2015)
10.1172/JCI38017
Antibody-based targeting of FGFR3 in bladder carcinoma and t(4;14)-positive multiple myeloma in mice.
J. Qing (2009)
10.1158/0008-5472.CAN-09-2552
MiR-15a and MiR-16 control Bmi-1 expression in ovarian cancer.
R. Bhattacharya (2009)
10.1016/j.devcel.2008.07.002
The endothelial-specific microRNA miR-126 governs vascular integrity and angiogenesis.
Shusheng Wang (2008)
10.1038/mt.2009.207
Systemic delivery of synthetic microRNA-16 inhibits the growth of metastatic prostate tumors via downregulation of multiple cell-cycle genes.
F. Takeshita (2010)
10.1016/j.jmoldx.2014.03.002
Diagnostic potential of miR-126, miR-143, miR-145, and miR-652 in malignant pleural mesothelioma.
M. Andersen (2014)
10.1016/j.bbrc.2013.08.032
Downregulation of microRNA-214 and overexpression of FGFR-1 contribute to hepatocellular carcinoma metastasis.
J. Wang (2013)
10.1200/JCO.2015.33.15_SUPPL.7500
Bevacizumab 15mg/kg plus cisplatin-pemetrexed (CP) triplet versus CP doublet in Malignant Pleural Mesothelioma (MPM): Results of the IFCT-GFPC-0701 MAPS randomized phase 3 trial.
G. Zalcman (2015)
Biology and treatment options
J. Li (2008)
10.1002/pros.20728
A neutralizing anti‐fibroblast growth factor (FGF) 8 monoclonal antibody shows anti‐tumor activity against FGF8b‐expressing LNCaP xenografts in androgen‐dependent and ‐independent conditions
Kumiko Maruyama-Takahashi (2008)
10.1158/1541-7786.MCR-14-0038
Nonamplified FGFR1 Is a Growth Driver in Malignant Pleural Mesothelioma
L. Marek (2014)
10.3892/ijo.2016.3358
Differential microRNA expression profiling of mesothelioma and expression analysis of miR-1 and miR-214 in mesothelioma.
V. Amatya (2016)
10.1158/1535-7163.MCT-15-0846
Trabectedin Is Active against Malignant Pleural Mesothelioma Cell and Xenograft Models and Synergizes with Chemotherapy and Bcl-2 Inhibition In Vitro
M. A. Hoda (2016)
10.1371/journal.pone.0105919
MET and PI3K/mTOR as a Potential Combinatorial Therapeutic Target in Malignant Pleural Mesothelioma
R. Kanteti (2014)
10.1164/rccm.201404-0658OC
Fibroblast growth factor receptor inhibition is active against mesothelioma and synergizes with radio- and chemotherapy.
K. Schelch (2014)
10.1097/JTO.0b013e3181ec18db
A Phase II Study of Sorafenib in Malignant Mesothelioma: Results of Cancer and Leukemia Group B 30307
S. Dubey (2010)
10.2174/138920109787315015
Tumor initiating cells.
N. Bansal (2009)
10.1158/1535-7163.MCT-14-0248
The Fibroblast Growth Factor Receptor Genetic Status as a Potential Predictor of the Sensitivity to CH5183284/Debio 1347, a Novel Selective FGFR Inhibitor
Y. Nakanishi (2014)
10.1158/0008-5472.CAN-09-3993
hsa-miR-29c* is linked to the prognosis of malignant pleural mesothelioma.
H. Pass (2010)
10.1007/s00280-007-0499-3
A small molecule pan-Bcl-2 family inhibitor, GX15-070, induces apoptosis and enhances cisplatin-induced apoptosis in non-small cell lung cancer cells
J. Li (2007)
miR - 15 a and miR - 16 are implicated in cell cycle regulation in a Rb - dependent manner and are frequently deleted or down - regulated in non - small cell lung cancer
N Bandi (2009)
10.1158/0008-5472.CAN-09-4479
Targeting fibroblast growth factor receptors blocks PI3K/AKT signaling, induces apoptosis, and impairs mammary tumor outgrowth and metastasis.
J. Dey (2010)
10.1006/METH.2001.1262
Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method.
K. Livak (2001)
The fibroblast growth factor receptor genetic status as a potential predictor of the sensitivity to CH5183284/Debio 1347, a novel selective FGFR
Y Nakanishi (2014)
10.1016/j.bbcan.2015.08.002
Lung cancer: Biology and treatment options.
H. Lemjabbar-Alaoui (2015)
10.1016/j.ccr.2011.01.040
Identification of a therapeutic strategy targeting amplified FGF19 in liver cancer by Oncogenomic screening.
Eric T Sawey (2011)
10.1186/s13287-017-0573-7
The inhibition of FGF receptor 1 activity mediates sorafenib antiproliferative effects in human malignant pleural mesothelioma tumor-initiating cells
A. Pattarozzi (2017)
10.1158/1541-7786.MCR-14-0442
Loss of miR-223 and JNK Signaling Contribute to Elevated Stathmin in Malignant Pleural Mesothelioma
Kimberly A. Birnie (2015)
10.1158/1078-0432.CCR-14-3357
FGFR1 Expression Levels Predict BGJ398 Sensitivity of FGFR1-Dependent Head and Neck Squamous Cell Cancers
F. Göke (2015)
10.1038/gt.2016.60
Cationic microRNA-delivering nanocarriers for efficient treatment of colon carcinoma in xenograft model
G. Liang (2016)
Bevacizumab 15 mg/kg plus cisplatin-pemetrexed (CP) triplet versus CP doublet in malignant pleural mesothelioma
G Zalcman (2015)
JNK Signaling Contribute to Elevated Stathmin in Malignant Pleural Mesothelioma
C. Blackwell (2016)
10.1038/bjc.2013.754
Enhanced FGFR signalling predisposes pancreatic cancer to the effect of a potent FGFR inhibitor in preclinical models
H. Zhang (2014)
10.1158/0008-5472.CAN-08-4277
miR-15a and miR-16 are implicated in cell cycle regulation in a Rb-dependent manner and are frequently deleted or down-regulated in non-small cell lung cancer.
N. Bandi (2009)



This paper is referenced by
The influence of selected polymorphisms in matrix metalloproteinases on response to treatment and disease progression in patients with mesothelioma
Danijela Štrbac (2019)
10.1016/j.canlet.2019.08.001
Exosomal transfer of miR-126 promotes the anti-tumour response in malignant mesothelioma: Role of miR-126 in cancer-stroma communication.
F. Monaco (2019)
10.3389/fgene.2020.00947
MicroRNA Expression Profiling of Bone Marrow–Derived Proangiogenic Cells (PACs) in a Mouse Model of Hindlimb Ischemia: Modulation by Classical Cardiovascular Risk Factors
M. Desjarlais (2020)
10.3390/cells8091091
Expression of FGFR1–4 in Malignant Pleural Mesothelioma Tissue and Corresponding Cell Lines and its Relationship to Patient Survival and FGFR Inhibitor Sensitivity
G. Vlacic (2019)
10.1016/J.GENREP.2018.06.012
Functions and epigenetic aspects of miR-15/16: Possible future cancer therapeutics
M. Ramaiah (2018)
10.1016/j.lfs.2020.118123
New vistas in malignant mesothelioma: MicroRNA architecture and NRF2/MAPK signal transduction.
Manav Gandhi (2020)
10.1016/j.omtn.2019.05.002
miR-15a/-16 Inhibit Angiogenesis by Targeting the Tie2 Coding Sequence: Therapeutic Potential of a miR-15a/16 Decoy System in Limb Ischemia
M. Besnier (2019)
10.1016/j.jtho.2018.02.021
State of the Art : Advances in Malignant Pleural Mesothelioma in 2017
Amanda J McCambridge (2018)
Targeting the Tie2 Coding Sequence: Therapeutic Potential of a miR-15a/16 Decoy System in Limb Ischemia. Molecular Therapy-Nucleic Acids, 17, 49-
M. Besnier (2019)
10.3389/fonc.2019.01293
Epigenetic Regulation of miRNA Expression in Malignant Mesothelioma: miRNAs as Biomarkers of Early Diagnosis and Therapy
M. Tomasetti (2019)
10.3389/fonc.2018.00650
MicroRNAs for the Diagnosis and Management of Malignant Pleural Mesothelioma: A Literature Review
G. Lo Russo (2018)
10.3892/or.2019.7033
Novel drug candidate for the treatment of several soft-tissue sarcoma histologic subtypes: A computational method using survival-associated gene signatures for drug repurposing
X. Yang (2019)
10.1038/s41419-020-02940-w
P53-regulated miR-320a targets PDL1 and is downregulated in malignant mesothelioma
C. Costa (2020)
10.1016/j.jtho.2018.02.021
Progress in the Management of Malignant Pleural Mesothelioma in 2017
Amanda J McCambridge (2018)
10.3390/ijms21176342
Genomics and Functional Genomics of Malignant Pleural Mesothelioma
Ece Çakıroğlu (2020)
10.1016/j.lungcan.2018.10.015
Assessment of signaling pathway inhibitors and identification of predictive biomarkers in malignant pleural mesothelioma.
R. Tranchant (2018)
Explorer miR-15 a /-16 Inhibit Angiogenesis by Targeting the Tie 2 Coding Sequence : Therapeutic Potential of a miR-15 a / 16 Decoy System in Limb Ischemia
M. Besnier (2019)
Semantic Scholar Logo Some data provided by SemanticScholar