title: miRNA-520f Reverses Epithelial-to-Mesenchymal Transition by TargetingADAM9andTGFBR2.
abstract: Reversing epithelial-to-mesenchymal transition (EMT) in cancer cells has been widely considered as an approach to combat cancer progression and therapeutic resistance, but a limited number of broadly comprehensive investigations of miRNAs involved in this process have been conducted. In this study, we screened a library of 1120 miRNA for their ability to transcriptionally activate the E-cadherin geneCDH1in a promoter reporter assay as a measure of EMT reversal. By this approach, we defined miR-520f as a novel EMT-reversing miRNA. miR-520f expression was sufficient to restore endogenous levels of E-cadherin in cancer cell lines exhibiting strong or intermediate mesenchymal phenotypes. In parallel, miR-520f inhibited invasive behavior in multiple cancer cell systems and reduced metastasis in an experimental mouse model of lung metastasis. Mechanistically, miR-520f inhibited tumor cell invasion by directly targetingADAM9, the TGFβ receptorTGFBR2and the EMT inducersZEB1, ZEB2, and the snail transcriptional repressorSNAI2, each crucial factors in mediating EMT. Collectively, our results show that miR-520f exerts anti-invasive and antimetastatic effectsin vitroandin vivo, warranting further study in clinical settings.Cancer Res; 77(8); 2008-17. ©2017 AACR.
authors.affiliation: Department of Urology, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, the Netherlands.
authors.forename: Jasmijn G M
authors.initials: JGM
authors.lastname: van Kampen
authors.affiliation: Department of Urology, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, the Netherlands.
authors.forename: Onno
authors.initials: O
authors.lastname: van Hooij
authors.affiliation: Department of Urology, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, the Netherlands.
authors.forename: Cornelius F
authors.initials: CF
authors.lastname: Jansen
authors.affiliation: MDxHealth B.V., Nijmegen, the Netherlands.
authors.forename: Frank P
authors.initials: FP
authors.lastname: Smit
authors.affiliation: InteRNA Technologies B.V., Utrecht, the Netherlands.
authors.forename: Paula I
authors.initials: PI
authors.lastname: van Noort
authors.affiliation: InteRNA Technologies B.V., Utrecht, the Netherlands.
authors.forename: Iman
authors.initials: I
authors.lastname: Schultz
authors.affiliation: InteRNA Technologies B.V., Utrecht, the Netherlands.
authors.forename: Roel Q J
authors.initials: RQJ
authors.lastname: Schaapveld
authors.affiliation: Department of Urology, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, the Netherlands.
authors.forename: Jack A
authors.initials: JA
authors.lastname: Schalken
authors.affiliation: Department of Urology, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, the Netherlands. Gerald.Verhaegh@radboudumc.nl.
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Verhaegh
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D000818:Animals; D015703:Antigens, CD; D015820:Cadherins / Q000235:genetics; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000008:administration & dosage* / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000235:genetics*; D015533:Transcriptional Activation; D014162:Transfection; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; C575048:MIRN520 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D051722:ADAM Proteins; C098339:ADAM9 protein, human