Mesenchymal MAPKAPK2/HSP27 drives intestinal carcinogenesis
Mesenchymal MAPKAPK2/HSP27 drives intestinal carcinogenesis
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DOI：
10.1073/pnas.1805683115
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发表时间：
2018-06-12
影响因子：
11.1
通讯作者：
Kollias, George
中科院分区：
文献类型：
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作者：
Henriques, Ana;Koliaraki, Vasiliki;Kollias, George
肿瘤微环境中的间充质细胞在肿瘤发生中发挥重要作用；然而，对介导这些影响的内在途径知之甚少。已知MAPK信号，如来自MAPKAPK2 （MK2）的信号可调节肿瘤发生，但其细胞特异性作用尚未确定。在这里，我们通过完全和条件消融MK2研究了MK2在肠道癌变中的细胞特异性作用。我们发现，在Apc（min/+）小鼠模型中，MK2的遗传和化学抑制均导致上皮细胞增殖降低，与肿瘤生长和侵袭潜力降低相关。值得注意的是，MK2的这种功能不是由其在免疫细胞中的免疫调节作用介导的。肠间充质细胞（IMCs）中MK2的缺失导致肿瘤多样性和生长的减少。在机制上，IMCs中的MK2是Hsp27磷酸化和下游致瘤效应分子产生所必需的，主要影响上皮细胞的增殖、凋亡和血管生成。与完全缺失MK2相比，在肠上皮细胞或内皮细胞中基因消融MK2的效果较差，分别通过调节上皮细胞凋亡和血管生成相关的增殖来减少肿瘤大小。在结肠炎相关癌变模型中也获得了类似的结果，表明MK2在该模型中也具有间质特异性作用。我们的研究结果证明了间充质特异性MK2/Hsp27轴在肿瘤发生中的核心致病作用，并强调了间充质MK2抑制在癌症治疗中的价值。
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 Apc(min/+) 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.