Mesenchymal MAPKAPK2/HSP27 drives intestinal carcinogenesis

Proceedings of the National Academy of Sciences of the United States of America
Ana HenriquesGeorge Kollias

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 apoptos...Continue Reading

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Citations

Mar 15, 2020·Cancers·Athena F PhoaLenka Munoz
Apr 27, 2019·Journal of Experimental & Clinical Cancer Research : CR·Sourabh SoniYogendra S Padwad
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Oct 3, 2019·Molecular Cancer Research : MCR·Rui WangHaiyang Yu
Oct 12, 2021·EMBO Reports·I-Ting ChenMing-Zong Lai

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