Dataset Information

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

ABSTRACT: Oxaliplatin (oxPt) resistance in colorectal cancers (CRC) is a major unsolved problem. Consequently, predictive markers and a better understanding of resistance mechanisms are urgently needed. To investigate if the recently identified predictive miR-625-3p is functionally involved in oxPt resistance, stable and inducible models of miR-625-3p dysregulation were analyzed. Ectopic expression of miR-625-3p in CRC cells led to increased resistance towards oxPt. The mitogen-activated protein kinase (MAPK) kinase 6 (MAP2K6/MKK6) – an activator of p38 MAPK - was identified as a functional target of miR-625-3p, and, in agreement, was down-regulated in patients not responding to oxPt therapy. The miR-625-3p resistance phenotype could be reversed by anti-miR-625-3p treatment and by ectopic expression of a miR-625-3p insensitive MAP2K6 variant. Transcriptome, proteome and phosphoproteome profiles revealed inactivation of MAP2K6-p38 signaling as a possible driving force behind oxPt resistance. We conclude that miR-625-3p induces oxPt resistance by abrogating MAP2K6-p38 regulated apoptosis and cell cycle control networks.

OTHER RELATED OMICS DATASETS IN: PRJNA324839PXD002172PRJNA324835

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Jesper Velgaard Olsen

PROVIDER: MSV000080762 | MassIVE | Wed Mar 29 11:17:00 BST 2017

SECONDARY ACCESSION(S): PXD002172

REPOSITORIES: MassIVE

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Publications

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

Rasmussen Mads Heilskov MH Lyskjær Iben I Jersie-Christensen Rosa Rakownikow RR Tarpgaard Line Schmidt LS Primdal-Bengtson Bjarke B Nielsen Morten Muhlig MM Pedersen Jakob Skou JS Hansen Tine Plato TP Hansen Flemming F Olsen Jesper Velgaard JV Olsen Jesper Velgaard JV Pfeiffer Per P Ørntoft Torben Falck TF Andersen Claus Lindbjerg CL

Nature communications 20160816

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 thera ...[more]

PMID: 27526785

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Project description:Highly pathogenic avian influenza viruses (HPAIV) induce severe inflammation in poultry and men. There is still an ongoing threat that these viruses may acquire the capability to freely spread as novel pandemic virus strains that may cause major morbidity and mortality. One characteristic of HPAIV infections is the induction of a cytokine burst that strongly contributes to viral pathogenicity. It has been suggested, that this cytokine overexpression is an intrinsic feature of infected cells and involves hyperinduction of p38 mitogen activated protein kinase (MAPK). Here we investigate the role of MAPK p38 signaling in the antiviral response against HPAIV in mice as well as in endothelial cells, the latter a primary source for cytokines during systemic infections. Global gene expression profiling of HPAIV infected endothelial cells in the presence of the MAP kinase p38-specific inhibitor SB202190 revealed, that inhibition of MAPK p38 leads to reduced expression of interferon (IFN) and other cytokines after A/Thailand/1(KAN-1)/2004 (H5N1) and A/FPV/Bratislava/79 (H7N7) infection. Furthermore, the expression of interferon stimulated genes (ISGs) after treatment with IFN or conditioned media from HPAIV infected cells was decreased when the target cells were preincubated with SB202190. Finally, promoter analysis confirmed a direct impact of p38 MAPK on the IFN-enhanceosome and ISG-promoter activity. In vivo inhibition of MAP kinase p38 greatly diminishes virus induced cytokine expression concomitant with reduced viral titers, thereby protecting mice from lethal infection. These observations show, that MAPK p38 acts on two levels of the antiviral IFN response: Initially the kinase regulates IFN induction and at a later stage MAPK p38 controls IFN signaling and thereby expression of IFN-stimulated genes. Thus, inhibition of MAP kinase p38 may be an antiviral strategy that significantly protects mice from lethal influenza via suppression of overshooting cytokine expression. HUVEC were infected with FPV in the presence or absence of a p38 MAP kinase inhibitor

Dataset Information

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

Publications

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

Similar Datasets

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