Proceedings of the National Academy of Sciences · 2018 · 41 citations · 38 references
MedicineCancer BiologyOncologyCarcinogenesisCell SignalingMolecular OncologyCancer Cell SignalingColorectal CancerGastrointestinal InflammationInflammation-associated CarcinogenesisInflammatory SignalingOncogenic Signaling PathwaysColitis-associated Colorectal CancerColorectal Carcinogenesis PathophysiologyImmunomodulatory EffectsInflammation-mediated CarcinogenesisMapk SignalingMek InhibitionMek InhibitorsTumor Metastasis Biology
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.
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Conditional gene targeting in macrophages and granulocytes using LysMcre mice
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APC mutations occur early during colorectal tumorigenesis
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