IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v7y2016i1d10.1038_ncomms12436.html
   My bibliography  Save this article

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

Author

Listed:
  • 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
    Present address: Institute for Clinical Medicine, University of Copenhagen, Kettegård Allé 30, DK-2650 Hvidovre, Denmark)

  • 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
    Odense University Hospital)

  • Torben Falck Ørntoft

    (Aarhus University Hospital)

  • Claus Lindbjerg Andersen

    (Aarhus University Hospital)

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.

Suggested Citation

  • Mads Heilskov Rasmussen & Iben Lyskjær & Rosa Rakownikow Jersie-Christensen & Line Schmidt Tarpgaard & Bjarke Primdal-Bengtson & Morten Muhlig Nielsen & Jakob Skou Pedersen & Tine Plato Hansen & Flemm, 2016. "miR-625-3p regulates oxaliplatin resistance by targeting MAP2K6-p38 signalling in human colorectal adenocarcinoma cells," Nature Communications, Nature, vol. 7(1), pages 1-15, November.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12436
    DOI: 10.1038/ncomms12436
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/ncomms12436
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/ncomms12436?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12436. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.