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. Experimental design for mass spectrometry SILAC experiments can be found at https://figshare.com/s/8e79f008e0e58ec6efc2 or https://doi.org/10.6084/m9.figshare.4888139

OTHER RELATED OMICS DATASETS IN: PRJNA324839MSV000080762PRJNA324835

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Rosa Jersie-Christensen

LAB HEAD: Jesper Velgaard Olsen

PROVIDER: PXD002172 | Pride | 2016-08-12

REPOSITORIES: Pride

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			Action	DRS
	20131226_QE5_UPLC10_RJC_COLLAB_AU_pEnrich_R01_E01_01.raw	Raw
	20131226_QE5_UPLC10_RJC_COLLAB_AU_pEnrich_R01_E01_02.raw	Raw
	20131226_QE5_UPLC10_RJC_COLLAB_AU_pEnrich_R01_E01_03.raw	Raw
	20131226_QE5_UPLC10_RJC_COLLAB_AU_pEnrich_R01_E02_01.raw	Raw
	20131226_QE5_UPLC10_RJC_COLLAB_AU_pEnrich_R01_E02_02.raw	Raw

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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:Background: circRNAs, a recently identified new member of non-coding RNAs, have been proved to play an essential role in the development and progression of various cancers. However, the functions and mechanisms of circRNAs in colorectal liver metastasis have not been fully elucidated. Methods: We performed circRNA microarray to screen differentially expressed novel circRNAs in the pathology of colorectal liver metastasis. Quantitative real-time PCR was used to detect the circ102049 expression in colorectal cancer (CRC) samples. Then CRC cells were transfected with a circ102049 over-expression vector or siRNAs, and the effects of circ102049 on biological functions in CRC cells were accessed in vitro. Mechanistically, the bioinformatics analysis, fluorescence in situ hybridization, RIP assay, RNA pull down assay and luciferase reporter assay were conducted to confirm the relationships among circ102049, miR-761, miR-192-3p and FRAS1. Moreover, the mechanism of circ102049 how to recruit and distribute DGCR8 protein in cytoplasm was elucidated. Results: The results showed that circ102049 was highly expressed in primary CRC tumors with liver metastasis and closely correlated with the CRC patients' prognosis. Circ102049 might act as a novel metastasis-related non-coding RNA, and significantly promote the adhesion, migration and invasion abilities of CRC cells. Mechanistically, we verified that circ102049 promoted the CRC development and progression via a miR-761/miR-192-3p-FRAS1-dependent mechanism. Notably, due to the distribution of DGCR8 protein, circ102049 might also reduce the mature products of miR-761 and miR-192-3p in cytoplasm indirectly. In addition, the role of circ102049 in promoting colorectal liver metastasis was also confirmed in vivo. Conclusions: Our findings provided new clues that circ102049 might be a potential prognostic factor in CRC, and the circ102049-miR-761/miR-192-3p-FRAS1 axis could be further explored as a therapeutic target for anti-metastatic therapy in CRC patients with liver metastases. Keywords: Hsa_circ_102049, miR-761, miR-192-3p, FRAS1, Colorectal liver metastasis