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.
Highlights
Oxaliplatin resistance in colorectal cancers (CRC) is a major medical problem, and predictive markers are urgently needed
We find that miR-625-3p-induced resistance is associated with reduced MAP kinase signal transduction after genotoxic stress leading to a reduction of p38-mediated apoptosis and an increase in cell cycle progression signals
We constructed a Sleeping Beauty (SB) transposon vector, which allows for stable expression of small interfering RNAs and miRNAs in a DOX-inducible manner (Supplementary Fig. 1), and robust downregulation of targeted genes in mammalian cells (Supplementary Fig. 2)
Summary
Oxaliplatin resistance in colorectal cancers (CRC) is a major medical problem, and predictive markers are urgently needed. We show that miR-625-3p functionally induces oxaliplatin resistance in CRC cells, and identify the signalling networks affected by miR-625-3p. 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. MiR-625-3p was reported to be positively associated with lack of response to first-line oxaliplatin (oxPt)-based treatment in two independent cohorts of patients with metastatic CRC (mCRC)[5]. While that study suggested high expression of miR-625-3p to be a novel predictive marker for oxPt-resistance in a subset of mCRC patients, a possible functional relationship between miR-625-3p and cellular drug sensitivity was not examined. We have identified direct and indirect targets of miR-625-3p dysregulation in these cells and in mCRC patients treated with first-line oxPt. We show that miR-625-3p directly targets and inhibits the mitogen activated protein kinase (MAPK) kinase MAP2K6 ( known as MKK6). We find that miR-625-3p-induced resistance is associated with reduced MAP kinase signal transduction after genotoxic stress leading to a reduction of p38-mediated apoptosis and an increase in cell cycle progression signals
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
