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 Citationer (Scopus)

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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.

Originalsprog	Engelsk
Artikelnummer	12436
Tidsskrift	Nature Communications
Vol/bind	7
Antal sider	15
ISSN	2041-1723
DOI	https://doi.org/10.1038/ncomms12436
Status	Udgivet - 16 aug. 2016

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10.1038/ncomms12436Licens: CC BY

miR-625-3p regulates oxaliplatin resistance by targeting MAP2K6-p38 signalling in human colorectal adenocarcinoma cellsForlagets udgivne version, 2,05 MBLicens: CC BY

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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, [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, bind 7, 12436. https://doi.org/10.1038/ncomms12436

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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.",

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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}",

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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 - 2016/8/16

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

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DO - 10.1038/ncomms12436

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SN - 2041-1723

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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

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