title: Tissue inhibitor of metalloproteinases-1 induces a pro-tumourigenic increase of miR-210 in lung adenocarcinoma cells and their exosomes.
abstract: Tissue inhibitor of metalloproteinases-1 (TIMP-1) recently emerged as a pro-metastatic factor highly associated with poor prognosis in a number of cancers. This correlation seemed paradox as TIMP-1 is best described as an inhibitor of pro-tumourigenic matrix metalloproteinases. Only recently, TIMP-1 has been revealed as a signalling molecule that can regulate cancer progression independent of its inhibitory properties. In the present study, we demonstrate that an increase of both exogenous and endogenous TIMP-1 led to the upregulation of miR-210 in a CD63/PI3K/AKT/HIF-1-dependent pathway in lung adenocarcinoma cells. TIMP-1 induced P110/P85 PI3K-signalling and AKT phosphorylation. It also led to increase of HIF-1α protein levels positively correlating with HIF-1-regulated mRNA expression and upregulation of the microRNA miR-210. Downstream targets of miR-210, namely FGFRL1, E2F3, VMP-1, RAD52 and SDHD, were decreased in the presence of TIMP-1. Upon the overexpression of TIMP-1 in tumour cells, miR-210 was accumulated in exosomes in vitro and in vivo. These exosomes promoted tube formation activity in human umbilical vein endothelial cell (HUVECs), which was reflected in increased angiogenesis in A549L-derived tumour xenografts. Activation and elevation of PI3K, AKT, HIF-1A and miR-210 in tumours additionally confirmed our in vitro data. This new pro-tumourigenic signalling function of TIMP-1 may explain why elevated TIMP-1 levels in lung cancer patients are highly correlated with poor prognosis.
authors.affiliation: Institut für Experimentelle Onkologie und Therapieforschung, Klinikum Rechts der Isar der Technischen Universität München, Ismaninger Straße 22, Munich, Germany.
authors.forename: H
authors.identifier: 0000000333588958
authors.initials: H
authors.lastname: Cui
authors.affiliation: Institut für Experimentelle Onkologie und Therapieforschung, Klinikum Rechts der Isar der Technischen Universität München, Ismaninger Straße 22, Munich, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Seubert
authors.affiliation: Physik Department, Walter Schottky Institute, Technische Universität München, Am Coulombwall 4a, Munich, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Stahl
authors.affiliation: Physik Department, Walter Schottky Institute, Technische Universität München, Am Coulombwall 4a, Munich, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Dietz
authors.affiliation: Klinische Forschergruppe der Frauenklinik, Klinikum Rechts der Isar der Technischen Universität München, Ismaninger Straße 22, Munich, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Reuning
authors.affiliation: 1] University of Nice Sophia-Antipolis, Nice, France [2] Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, UMR 6097 CNRS/UNSA, Sophia Antipolis, France.
authors.forename: L
authors.initials: L
authors.lastname: Moreno-Leon
authors.affiliation: 1] University of Nice Sophia-Antipolis, Nice, France [2] Laboratory of Clinical and Experimental Pathology and Hospital Integrated Biobank, Centre Hospitalier Universitaire de Nice, Nice, France.
authors.forename: M
authors.initials: M
authors.lastname: Ilie
authors.affiliation: 1] University of Nice Sophia-Antipolis, Nice, France [2] Laboratory of Clinical and Experimental Pathology and Hospital Integrated Biobank, Centre Hospitalier Universitaire de Nice, Nice, France.
authors.forename: P
authors.initials: P
authors.lastname: Hofman
authors.affiliation: Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Muscolosketal Sciences, University of Oxford, London, UK.
authors.forename: H
authors.initials: H
authors.lastname: Nagase
authors.affiliation: 1] University of Nice Sophia-Antipolis, Nice, France [2] Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, UMR 6097 CNRS/UNSA, Sophia Antipolis, France.
authors.forename: B
authors.initials: B
authors.lastname: Mari
authors.affiliation: Institut für Experimentelle Onkologie und Therapieforschung, Klinikum Rechts der Isar der Technischen Universität München, Ismaninger Straße 22, Munich, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Krüger
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism*; D000077192:Adenocarcinoma of Lung; D000818:Animals; D045744:Cell Line, Tumor; D055354:Exosomes / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D009368:Neoplasm Transplantation; D015398:Signal Transduction; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: C543800:MIRN210 microRNA, human; D035683:MicroRNAs; C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1