MiR-625-3p Regulates Oxaliplatin Resistance by Targeting MAP2K6-p38 Signalling in Human Colorectal Adenocarcinoma Cells

Overview

Journal Nat Commun

Specialty Biology

Date 2016 Aug 17

PMID 27526785

Citations 50

Authors

Mads Heilskov Rasmussen

Iben Lyskjaer

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 Orntoft

Claus Lindbjerg Andersen

Affiliations

Soon will be listed here.

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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References

Archambault V, Glover D . Polo-like kinases: conservation and divergence in their functions and regulation. Nat Rev Mol Cell Biol. 2009; 10(4):265-75. DOI: 10.1038/nrm2653. View

Blower P, Chung J, Verducci J, Lin S, Park J, Dai Z . MicroRNAs modulate the chemosensitivity of tumor cells. Mol Cancer Ther. 2008; 7(1):1-9. DOI: 10.1158/1535-7163.MCT-07-0573. View

Liu G, Zhang Y, Bode A, Ma W, Dong Z . Phosphorylation of 4E-BP1 is mediated by the p38/MSK1 pathway in response to UVB irradiation. J Biol Chem. 2002; 277(11):8810-6. DOI: 10.1074/jbc.M110477200. View

Subramanian A, Tamayo P, Mootha V, Mukherjee S, Ebert B, Gillette M . Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005; 102(43):15545-50. PMC: 1239896. DOI: 10.1073/pnas.0506580102. View

Pereira L, Igea A, Canovas B, Dolado I, Nebreda A . Inhibition of p38 MAPK sensitizes tumour cells to cisplatin-induced apoptosis mediated by reactive oxygen species and JNK. EMBO Mol Med. 2013; 5(11):1759-74. PMC: 3840490. DOI: 10.1002/emmm.201302732. View

Meerbrey K, Hu G, Kessler J, Roarty K, Li M, Fang J . The pINDUCER lentiviral toolkit for inducible RNA interference in vitro and in vivo. Proc Natl Acad Sci U S A. 2011; 108(9):3665-70. PMC: 3048138. DOI: 10.1073/pnas.1019736108. View

Hernandez Losa J, Parada Cobo C, Viniegra J, Sanchez-Arevalo Lobo V, Cajal S, Sanchez-Prieto R . Role of the p38 MAPK pathway in cisplatin-based therapy. Oncogene. 2003; 22(26):3998-4006. DOI: 10.1038/sj.onc.1206608. View

Shevchenko A, Tomas H, Havlis J, Olsen J, Mann M . In-gel digestion for mass spectrometric characterization of proteins and proteomes. Nat Protoc. 2007; 1(6):2856-60. DOI: 10.1038/nprot.2006.468. View

Su H, Trombly M, Chen J, Wang X . Essential and overlapping functions for mammalian Argonautes in microRNA silencing. Genes Dev. 2009; 23(3):304-17. PMC: 2648544. DOI: 10.1101/gad.1749809. View

10.

Pines A, Kelstrup C, Vrouwe M, Puigvert J, Typas D, Misovic B . Global phosphoproteome profiling reveals unanticipated networks responsive to cisplatin treatment of embryonic stem cells. Mol Cell Biol. 2011; 31(24):4964-77. PMC: 3233030. DOI: 10.1128/MCB.05258-11. View

11.

Kelstrup C, Jersie-Christensen R, Batth T, Arrey T, Kuehn A, Kellmann M . Rapid and deep proteomes by faster sequencing on a benchtop quadrupole ultra-high-field Orbitrap mass spectrometer. J Proteome Res. 2014; 13(12):6187-95. DOI: 10.1021/pr500985w. View

12.

Zanke B, Rubie E, Winnett E, Chan J, Randall S, Parsons M . Mammalian mitogen-activated protein kinase pathways are regulated through formation of specific kinase-activator complexes. J Biol Chem. 1996; 271(47):29876-81. DOI: 10.1074/jbc.271.47.29876. View

13.

de Hoon M, Imoto S, Nolan J, Miyano S . Open source clustering software. Bioinformatics. 2004; 20(9):1453-4. DOI: 10.1093/bioinformatics/bth078. View

14.

Liu H, Hu H, Chao J . Oxaliplatin down-regulates survivin by p38 MAP kinase and proteasome in human colon cancer cells. Chem Biol Interact. 2010; 188(3):535-45. DOI: 10.1016/j.cbi.2010.08.001. View

15.

Owens D, Keyse S . Differential regulation of MAP kinase signalling by dual-specificity protein phosphatases. Oncogene. 2007; 26(22):3203-13. DOI: 10.1038/sj.onc.1210412. View

16.

Raingeaud J, Whitmarsh A, Barrett T, Derijard B, Davis R . MKK3- and MKK6-regulated gene expression is mediated by the p38 mitogen-activated protein kinase signal transduction pathway. Mol Cell Biol. 1996; 16(3):1247-55. PMC: 231107. DOI: 10.1128/MCB.16.3.1247. View

17.

Derbyshire Z, Halfter U, Heimark R, Sy T, Vaillancourt R . Angiotensin II stimulated transcription of cyclooxygenase II is regulated by a novel kinase cascade involving Pyk2, MEKK4 and annexin II. Mol Cell Biochem. 2005; 271(1-2):77-90. DOI: 10.1007/s11010-005-5386-9. View

18.

Heald R, McKeon F . Mutations of phosphorylation sites in lamin A that prevent nuclear lamina disassembly in mitosis. Cell. 1990; 61(4):579-89. DOI: 10.1016/0092-8674(90)90470-y. View

19.

Germani A, Matrone A, Grossi V, Peserico A, Sanese P, Liuzzi M . Targeted therapy against chemoresistant colorectal cancers: Inhibition of p38α modulates the effect of cisplatin in vitro and in vivo through the tumor suppressor FoxO3A. Cancer Lett. 2013; 344(1):110-118. DOI: 10.1016/j.canlet.2013.10.035. View

20.

Remy G, Risco A, Inesta-Vaquera F, Gonzalez-Teran B, Sabio G, Davis R . Differential activation of p38MAPK isoforms by MKK6 and MKK3. Cell Signal. 2009; 22(4):660-7. DOI: 10.1016/j.cellsig.2009.11.020. View