title: miR-515-5p controls cancer cell migration through MARK4 regulation.
abstract: Here, we show that miR-515-5p inhibits cancer cell migration and metastasis. RNA-seq analyses of both oestrogen receptor receptor-positive and receptor-negative breast cancer cells overexpressing miR-515-5p reveal down-regulation of NRAS, FZD4, CDC42BPA, PIK3C2B and MARK4 mRNAs. We demonstrate that miR-515-5p inhibits MARK4 directly 3' UTR interaction and that MARK4 knock-down mimics the effect of miR-515-5p on breast and lung cancer cell migration. MARK4 overexpression rescues the inhibitory effects of miR-515-5p, suggesting miR-515-5p mediates this process through MARK4 down-regulation. Furthermore, miR-515-5p expression is reduced in metastases compared to primary tumours derived from both in vivo xenografts and samples from patients with breast cancer. Conversely, miR-515-5p overexpression prevents tumour cell dissemination in a mouse metastatic model. Moreover, high miR-515-5p and low MARK4 expression correlate with increased breast and lung cancer patients' survival, respectively. Taken together, these data demonstrate the importance of miR-515-5p/MARK4 regulation in cell migration and metastasis across two common cancers.
authors.affiliation: Department of Surgery & Cancer, Division of Cancer, Imperial Centre for Translational and Experimental Medicine (ICTEM), Imperial College Hammersmith Hospital Campus, London, UK o.pardo@imperial.ac.uk m.seckl@imperial.ac.uk j.stebbing@imperial.ac.uk.
authors.forename: Olivier E
authors.initials: OE
authors.lastname: Pardo
authors.affiliation: Department of Surgery & Cancer, Division of Cancer, Imperial Centre for Translational and Experimental Medicine (ICTEM), Imperial College Hammersmith Hospital Campus, London, UK.
authors.forename: Leandro
authors.initials: L
authors.lastname: Castellano
authors.affiliation: Department of Surgery & Cancer, Division of Cancer, Imperial Centre for Translational and Experimental Medicine (ICTEM), Imperial College Hammersmith Hospital Campus, London, UK.
authors.forename: Catriona E
authors.initials: CE
authors.lastname: Munro
authors.affiliation: Department of Oncology, Imperial College Healthcare NHS Trust Charing Cross Hospital, London, UK.
authors.forename: Yili
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Surgery & Cancer, Division of Cancer, Imperial Centre for Translational and Experimental Medicine (ICTEM), Imperial College Hammersmith Hospital Campus, London, UK.
authors.forename: Francesco
authors.initials: F
authors.lastname: Mauri
authors.affiliation: Department of Surgery & Cancer, Division of Cancer, Imperial Centre for Translational and Experimental Medicine (ICTEM), Imperial College Hammersmith Hospital Campus, London, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Krell
authors.affiliation: Department of Surgery & Cancer, Division of Cancer, Imperial Centre for Translational and Experimental Medicine (ICTEM), Imperial College Hammersmith Hospital Campus, London, UK.
authors.forename: Romain
authors.initials: R
authors.lastname: Lara
authors.affiliation: Department of Surgery & Cancer, Division of Cancer, Imperial Centre for Translational and Experimental Medicine (ICTEM), Imperial College Hammersmith Hospital Campus, London, UK.
authors.forename: Filipa G
authors.initials: FG
authors.lastname: Pinho
authors.affiliation: Department of Surgery & Cancer, Division of Cancer, Imperial Centre for Translational and Experimental Medicine (ICTEM), Imperial College Hammersmith Hospital Campus, London, UK.
authors.forename: Thameenah
authors.initials: T
authors.lastname: Choudhury
authors.affiliation: Department of Surgery & Cancer, Division of Cancer, Imperial Centre for Translational and Experimental Medicine (ICTEM), Imperial College Hammersmith Hospital Campus, London, UK.
authors.forename: Adam E
authors.initials: AE
authors.lastname: Frampton
authors.affiliation: Department of Surgery & Cancer, Division of Cancer, Imperial Centre for Translational and Experimental Medicine (ICTEM), Imperial College Hammersmith Hospital Campus, London, UK.
authors.forename: Loredana
authors.initials: L
authors.lastname: Pellegrino
authors.affiliation: Department of Surgery & Cancer, Division of Cancer, Imperial Centre for Translational and Experimental Medicine (ICTEM), Imperial College Hammersmith Hospital Campus, London, UK.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Pshezhetskiy
authors.affiliation: Department of Oncology, Imperial College Healthcare NHS Trust Charing Cross Hospital, London, UK.
authors.forename: Yulan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Surgery & Cancer, Division of Cancer, Imperial Centre for Translational and Experimental Medicine (ICTEM), Imperial College Hammersmith Hospital Campus, London, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Waxman
authors.affiliation: Department of Surgery & Cancer, Division of Cancer, Imperial Centre for Translational and Experimental Medicine (ICTEM), Imperial College Hammersmith Hospital Campus, London, UK Key Laboratory of Magnetic Resonance in Biological Systems, Wuhan Center for Magnetic Resonance, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Wuhan Institute of Physics and Mathematics Chinese Academy of Sciences, Wuhan, China o.pardo@imperial.ac.uk m.seckl@imperial.ac.uk j.stebbing@imperial.ac.uk.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Seckl
authors.affiliation: Department of Surgery & Cancer, Division of Cancer, Imperial Centre for Translational and Experimental Medicine (ICTEM), Imperial College Hammersmith Hospital Campus, London, UK Key Laboratory of Magnetic Resonance in Biological Systems, Wuhan Center for Magnetic Resonance, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Wuhan Institute of Physics and Mathematics Chinese Academy of Sciences, Wuhan, China o.pardo@imperial.ac.uk m.seckl@imperial.ac.uk j.stebbing@imperial.ac.uk.
authors.forename: Justin
authors.initials: J
authors.lastname: Stebbing
mesh_terms: D000072283:A549 Cells; D000818:Animals; D017209:Apoptosis; D001943:Breast Neoplasms / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation / Q000235:genetics; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics; D061986:MCF-7 Cells; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D012333:RNA, Messenger
chemical_list: C585821:MIRN515 microRNA, human; D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; D012333:RNA, Messenger; C483047:MARK4 protein, human; C482979:MARK4 protein, mouse; D017346:Protein Serine-Threonine Kinases
keywords: breast cancer; lung cancer; miR‐515‐5p; microRNAs; microtubule affinity‐regulating kinase 4