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; Claus Lindbjerg Andersen

doi:10.1038/ncomms12436

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, Claus Lindbjerg Andersen

43 Citations (Scopus)

74 Downloads (Pure)

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.

Original language	English
Article number	12436
Journal	Nature Communications
Volume	7
Number of pages	15
ISSN	2041-1723
DOIs	https://doi.org/10.1038/ncomms12436
Publication status	Published - 16 Aug 2016

Keywords

Journal Article

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/ncomms12436Licence: CC BY

miR-625-3p regulates oxaliplatin resistance by targeting MAP2K6-p38 signalling in human colorectal adenocarcinoma cellsFinal published version, 2.05 MBLicence: CC BY

Cite this

Rasmussen, M. H., Lyskjær, I., Jersie-Christensen, R. R., Tarpgaard, L. S., Primdal-Bengtson, B., Nielsen, M. M., Pedersen, J. S., Hansen, T. P., Hansen, F., Olsen, J. V., Pfeiffer, P., Ørntoft, T. F., & Andersen, C. L. (2016). miR-625-3p regulates oxaliplatin resistance by targeting MAP2K6-p38 signalling in human colorectal adenocarcinoma cells. Nature Communications, 7, Article 12436. https://doi.org/10.1038/ncomms12436

Rasmussen, MH, Lyskjær, I, Jersie-Christensen, RR, Tarpgaard, LS, Primdal-Bengtson, B, Nielsen, MM, Pedersen, JS, Hansen, TP, Hansen, F, Olsen, JV, Pfeiffer, P, Ørntoft, TF & Andersen, CL 2016, 'miR-625-3p regulates oxaliplatin resistance by targeting MAP2K6-p38 signalling in human colorectal adenocarcinoma cells', Nature Communications, vol. 7, 12436. https://doi.org/10.1038/ncomms12436

@article{0bccf696215d4aafb216742f0a5007cd,

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.",

keywords = "Journal Article",

author = "Rasmussen, {Mads Heilskov} and Iben Lyskj{\ae}r and Jersie-Christensen, {Rosa Rakownikow} and Tarpgaard, {Line Schmidt} and Bjarke Primdal-Bengtson and Nielsen, {Morten Muhlig} and Pedersen, {Jakob Skou} and Hansen, {Tine Plato} and Flemming Hansen and Olsen, {Jesper Velgaard} and Per Pfeiffer and {\O}rntoft, {Torben Falck} and Andersen, {Claus Lindbjerg}",

year = "2016",

month = aug,

day = "16",

doi = "10.1038/ncomms12436",

language = "English",

volume = "7",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "nature publishing group",

}

TY - JOUR

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 - 2016/8/16

Y1 - 2016/8/16

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

SN - 2041-1723

VL - 7

JO - Nature Communications

JF - Nature Communications

M1 - 12436

ER -

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

Abstract

Keywords

UN SDGs

Access to Document

Fingerprint

Cite this