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Proc Natl Acad Sci U S A. 2018 Jun 12;115(24):E5546-E5555. doi: 10.1073/pnas.1805683115. Epub 2018 May 29.

Mesenchymal MAPKAPK2/HSP27 drives intestinal carcinogenesis.

Author information

1
Department of Immunology, Biomedical Sciences Research Centre "Alexander Fleming," 16672 Vari, Greece.
2
Department of Immunology, Biomedical Sciences Research Centre "Alexander Fleming," 16672 Vari, Greece; koliaraki@fleming.gr kollias@fleming.gr.
3
Department of Physiology, Medical School, University of Athens, 11527 Athens, Greece.

Abstract

Mesenchymal cells in the microenvironment of cancer exert important functions in tumorigenesis; however, little is known of intrinsic pathways that mediate these effects. MAPK signals, such as from MAPKAPK2 (MK2) are known to modulate tumorigenesis, yet their cell-specific role has not been determined. Here, we studied the cell-specific role of MK2 in intestinal carcinogenesis using complete and conditional ablation of MK2. We show that both genetic and chemical inhibition of MK2 led to decreased epithelial cell proliferation, associated with reduced tumor growth and invasive potential in the Apcmin/+ mouse model. Notably, this function of MK2 was not mediated by its well-described immunomodulatory role in immune cells. Deletion of MK2 in intestinal mesenchymal cells (IMCs) led to both reduced tumor multiplicity and growth. Mechanistically, MK2 in IMCs was required for Hsp27 phosphorylation and the production of downstream tumorigenic effector molecules, dominantly affecting epithelial proliferation, apoptosis, and angiogenesis. Genetic ablation of MK2 in intestinal epithelial or endothelial cells was less effective in comparison with its complete deletion, leading to reduction of tumor size via modulation of epithelial apoptosis and angiogenesis-associated proliferation, respectively. Similar results were obtained in a model of colitis-associated carcinogenesis, indicating a mesenchymal-specific role for MK2 also in this model. Our findings demonstrate the central pathogenic role of mesenchymal-specific MK2/Hsp27 axis in tumorigenesis and highlight the value of mesenchymal MK2 inhibition in the treatment of cancer.

KEYWORDS:

MAP kinases; colorectal cancer; stromal cells; tumor microenvironment

PMID:
29844172
PMCID:
PMC6004446
DOI:
10.1073/pnas.1805683115
[Indexed for MEDLINE]
Free PMC Article

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