miR-625-3p regulates oxaliplatin resistance by targeting MAP2K6-p38 signalling in human colorectal adenocarcinoma cells

Mads Heilskov Rasmussen, Iben Lyskjær, Rosa Rakownikow Jersie-Christensen, Line Schmidt Tarpgaard, Bjarke Primdal-Bengtson, Morten Muhlig Nielsen, Jakob Skou Pedersen, Tine Plato Hansen, Flemming Hansen, Jesper Velgaard Olsen, Per Pfeiffer, Torben Falck Ørntoft and Claus Lindbjerg Andersen ()
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Mads Heilskov Rasmussen: Aarhus University Hospital
Iben Lyskjær: Aarhus University Hospital
Rosa Rakownikow Jersie-Christensen: Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Protein Research, University of Copenhagen
Line Schmidt Tarpgaard: Institute of Clinical Research, University of Southern Denmark
Bjarke Primdal-Bengtson: Aarhus University Hospital
Morten Muhlig Nielsen: Aarhus University Hospital
Jakob Skou Pedersen: Aarhus University Hospital
Tine Plato Hansen: Institute of Clinical Research, Odense University Hospital
Flemming Hansen: Aarhus University Hospital
Jesper Velgaard Olsen: Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Protein Research, University of Copenhagen
Per Pfeiffer: Institute of Clinical Research, University of Southern Denmark
Torben Falck Ørntoft: Aarhus University Hospital
Claus Lindbjerg Andersen: Aarhus University Hospital

Nature Communications, 2016, vol. 7, issue 1, 1-15

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12436

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