title: miR-625-3p regulates oxaliplatin resistance by targeting MAP2K6-p38 signalling in human colorectal adenocarcinoma cells.
abstract: Oxaliplatin resistance in colorectal cancers (CRC) is a major medical problem, and predictive markers are urgently needed. Recently, miR-625-3p was reported as a promising predictive marker. Herein, we show that miR-625-3p functionally induces oxaliplatin resistance in CRC cells, and identify the signalling networks affected by miR-625-3p. We show that the p38 MAPK activator MAP2K6 is a direct target of miR-625-3p, and, accordingly, is downregulated in non-responder patients of oxaliplatin therapy. miR-625-3p-mediated resistance is reversed by anti-miR-625-3p treatment and ectopic expression of a miR-625-3p insensitive MAP2K6 variant. In addition, reduction of p38 signalling by using siRNAs, chemical inhibitors or expression of a dominant-negative MAP2K6 protein induces resistance to oxaliplatin. Transcriptome, proteome and phosphoproteome profiles confirm inactivation of MAP2K6-p38 signalling as one likely mechanism of oxaliplatin resistance. Our study shows that miR-625-3p induces oxaliplatin resistance by abrogating MAP2K6-p38-regulated apoptosis and cell cycle control networks, and corroborates the predictive power of miR-625-3p.
authors.affiliation: Department of Molecular Medicine, Department of Clinical Medicine, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, DK-8200 Aarhus, Denmark.
authors.forename: Mads Heilskov
authors.initials: MH
authors.lastname: Rasmussen
authors.affiliation: Department of Molecular Medicine, Department of Clinical Medicine, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, DK-8200 Aarhus, Denmark.
authors.forename: Iben
authors.initials: I
authors.lastname: Lyskjær
authors.affiliation: Department of Proteomics, Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Blegdamsvej 3b, DK-2200 Copenhagen, Denmark.
authors.forename: Rosa Rakownikow
authors.initials: RR
authors.lastname: Jersie-Christensen
authors.affiliation: Institute of Clinical Research, University of Southern Denmark, Winsløwparken 19, DK-5000 Odense, Denmark.
authors.forename: Line Schmidt
authors.initials: LS
authors.lastname: Tarpgaard
authors.affiliation: Department of Molecular Medicine, Department of Clinical Medicine, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, DK-8200 Aarhus, Denmark.
authors.forename: Bjarke
authors.initials: B
authors.lastname: Primdal-Bengtson
authors.affiliation: Department of Molecular Medicine, Department of Clinical Medicine, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, DK-8200 Aarhus, Denmark.
authors.forename: Morten Muhlig
authors.initials: MM
authors.lastname: Nielsen
authors.affiliation: Department of Molecular Medicine, Department of Clinical Medicine, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, DK-8200 Aarhus, Denmark.
authors.forename: Jakob Skou
authors.identifier: 0000-0002-7236-4001
authors.initials: JS
authors.lastname: Pedersen
authors.affiliation: Department of Pathology, Institute of Clinical Research, Odense University Hospital, Winsløwparken 15, DK-5000 Odense, Denmark.
authors.forename: Tine Plato
authors.initials: TP
authors.lastname: Hansen
authors.affiliation: Department of Oncology, Aarhus University Hospital, Nørrebrogade 44, DK-8200 Aarhus, Denmark.
authors.forename: Flemming
authors.initials: F
authors.lastname: Hansen
authors.affiliation: Department of Proteomics, Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Blegdamsvej 3b, DK-2200 Copenhagen, Denmark.
authors.forename: Jesper Velgaard
authors.initials: JV
authors.lastname: Olsen
authors.affiliation: Institute of Clinical Research, University of Southern Denmark, Winsløwparken 19, DK-5000 Odense, Denmark.|Department of Oncology, Odense University Hospital, Sdr. Boulevard 29, DK-5000 Odense, Denmark.
authors.forename: Per
authors.initials: P
authors.lastname: Pfeiffer
authors.affiliation: Department of Molecular Medicine, Department of Clinical Medicine, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, DK-8200 Aarhus, Denmark.
authors.forename: Torben Falck
authors.initials: TF
authors.lastname: Ørntoft
authors.affiliation: Department of Molecular Medicine, Department of Clinical Medicine, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, DK-8200 Aarhus, Denmark.
authors.forename: Claus Lindbjerg
authors.initials: CL
authors.lastname: Andersen
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D048669:MAP Kinase Kinase 6 / Q000235:genetics* / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics*; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D020543:Proteome / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C575476:MIRN625 microRNA, human; D035683:MicroRNAs; D009944:Organoplatinum Compounds; D020543:Proteome; D000077150:Oxaliplatin; D048051:p38 Mitogen-Activated Protein Kinases; D048669:MAP Kinase Kinase 6; C482566:MAP2K6 protein, human