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Nat Commun. 2017 Oct 16;8(1):947. doi: 10.1038/s41467-017-00983-w.

TRPA1-FGFR2 binding event is a regulatory oncogenic driver modulated by miRNA-142-3p.

Author information

1
School of Molecular and Cellular Biology, University of Leeds, Leeds, LS2 9JT, UK.
2
Division of Clinical Chemistry and Pharmacology, Lund University, 221 85, Lund, Sweden.
3
School of Biomedical Sciences, University of Leeds, Leeds, LS2 9JT, UK.
4
The University of Texas at Brownsville, Brownsville, TX, 78520, USA.
5
Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77054, USA.
6
Leeds Institute of Cancer and Pathology, Wellcome Trust Brenner Building, St James's University Hospital, LS9 7TF, Leeds, UK.
7
Faculty of Medicine and Health, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, LS2 9JT, UK.
8
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77054, USA.
9
Faculty of Medicine and Health, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, LS2 9JT, UK.
10
Centre for Biotechnology, Anna University, Chennai, Tamil Nadu, 600025, India.
11
Department of Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, Unit 63, Houston, TX, 77054, USA.
12
Section of Pathology and Tumor Biology, Leeds Institute of Cancer and Pathology, Wellcome Trust Brenner Building, St James's University Hospital, Leeds, LS9 7TF, UK.
13
Department of Physics, King's College London, Strand, London, WC2R 2LS, UK.
14
Cancer Research UK Edinburgh Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XR, UK.
15
Institute of Pharmaceutical Science, Franklin-Wilkins Building, King's College London, London, SE1 9NH, UK.
16
Department of Experimental Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77054, USA.
17
School of Molecular and Cellular Biology, University of Leeds, Leeds, LS2 9JT, UK. Z.Timsah@leeds.ac.uk.

Abstract

Recent evidence suggests that the ion channel TRPA1 is implicated in lung adenocarcinoma (LUAD), where its role and mechanism of action remain unknown. We have previously established that the membrane receptor FGFR2 drives LUAD progression through aberrant protein-protein interactions mediated via its C-terminal proline-rich motif. Here we report that the N-terminal ankyrin repeats of TRPA1 directly bind to the C-terminal proline-rich motif of FGFR2 inducing the constitutive activation of the receptor, thereby prompting LUAD progression and metastasis. Furthermore, we show that upon metastasis to the brain, TRPA1 gets depleted, an effect triggered by the transfer of TRPA1-targeting exosomal microRNA (miRNA-142-3p) from brain astrocytes to cancer cells. This downregulation, in turn, inhibits TRPA1-mediated activation of FGFR2, hindering the metastatic process. Our study reveals a direct binding event and characterizes the role of TRPA1 ankyrin repeats in regulating FGFR2-driven oncogenic process; a mechanism that is hindered by miRNA-142-3p.TRPA1 has been reported to contribute lung cancer adenocarcinoma (LUAD), but the mechanisms are unclear. Here the authors propose that TRPA1/FGFR2 interaction is functional in LUAD and show that astrocytes oppose brain metastasis by mediating the downregulation of TRPA1 through exosome-delivered miRNA-142-3p.

PMID:
29038531
PMCID:
PMC5643494
DOI:
10.1038/s41467-017-00983-w
[Indexed for MEDLINE]
Free PMC Article

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