miR-625-3p regulates oxaliplatin resistance by targeting MAP2K6-p38 signalling in human colorectal adenocarcinoma cells
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miR-625-3p regulates oxaliplatin resistance by targeting MAP2K6-p38 signalling in human colorectal adenocarcinoma cells. / Rasmussen, Mads Heilskov; Lyskjær, Iben; Jersie-Christensen, Rosa Rakownikow; Tarpgaard, Line Schmidt; Primdal-Bengtson, Bjarke; Nielsen, Morten Muhlig; Pedersen, Jakob Skou; Hansen, Tine Plato; Hansen, Flemming; Olsen, Jesper Velgaard; Pfeiffer, Per; Ørntoft, Torben Falck; Andersen, Claus Lindbjerg.
I: Nature Communications, Bind 7, 12436, 2016.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - miR-625-3p regulates oxaliplatin resistance by targeting MAP2K6-p38 signalling in human colorectal adenocarcinoma cells
AU - Rasmussen, Mads Heilskov
AU - Lyskjær, Iben
AU - Jersie-Christensen, Rosa Rakownikow
AU - Tarpgaard, Line Schmidt
AU - Primdal-Bengtson, Bjarke
AU - Nielsen, Morten Muhlig
AU - Pedersen, Jakob Skou
AU - Hansen, Tine Plato
AU - Hansen, Flemming
AU - Olsen, Jesper Velgaard
AU - Pfeiffer, Per
AU - Ørntoft, Torben Falck
AU - Andersen, Claus Lindbjerg
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
KW - Journal Article
U2 - 10.1038/ncomms12436
DO - 10.1038/ncomms12436
M3 - Journal article
C2 - 27526785
VL - 7
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
M1 - 12436
ER -
ID: 164828958