AMPKalpha2 knockout enhances tumour inflammation through exacerbated liver injury and energy deprivation-associated AMPKalpha1 activation.
AMPKalpha2 knockout enhances tumour inflammation through exacerbated liver injury and energy deprivation-associated AMPKalpha1 activation.
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AMPKalpha2 敲除会通过加剧肝损伤和能量剥夺相关的 AMPKalpha1 激活来增强肿瘤炎症。
DOI：
10.1111/jcmm.13978
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发表时间：
2019
影响因子：
5.3
通讯作者：
Du Jie
中科院分区：
文献类型：
--
作者：
Qiu Shulan;Liu Taoyan;Piao Chunmei;Wang Ying;Wang Kefang;Zhou Y;ong;Cai Lun;Zheng Shuai;Lan Feng;Du Jie
组织损伤及其相关炎症是肿瘤的启动因子或传播者。AMP激活的蛋白激酶（AMPK）被环境或营养应激因素激活，如缺氧、葡萄糖剥夺和其他细胞损伤因素，以调节细胞能量平衡和分化。我们之前报道过AMPKα2缺乏导致荷瘤肝脏能量剥夺和肝细胞死亡增加。本研究通过敲除AMPKα2小鼠和结肠癌细胞肝转移模型来研究AMPKα亚型在肿瘤炎症中的作用。首先，我们发现AMPKα2缺失加重了肝损伤和巨噬细胞的募集。同时，虽然敲除AMPKα2后AMPKα1代偿性表达不显著，但敲除AMPKα2小鼠残肝中AMPKα1磷酸化水平升高，这与AMPKα2缺失小鼠能量剥夺增强呈正相关。此外，巨噬细胞中活化的AMPKα1有助于其向肿瘤相关表型极化。因此，AMPKα2缺陷小鼠肿瘤相关炎症的增强和AMPKα1的激活可能通过影响肿瘤炎症微环境来加剧肿瘤的发展。我们的研究表明，AMPKα的两种亚型，AMPKα1和AMPKα2在控制肿瘤发展中发挥着不同的作用。
Tissue damage and its associated‐inflammation act as tumour initiators or propagators. AMP‐activated protein kinase (AMPK) is activated by environmental or nutritional stress factors, such as hypoxia, glucose deprivation, and other cell injury factors, to regulate cell energy balance and differentiation. We previously have reported that AMPKα2 deficiency resulted in the energy deprivation in tumour‐bearing liver and the enhanced‐hepatocyte death. In this study, AMPKα2 knockout mice and the liver metastasis model of colon cancer cells were used to address the role of AMPKα isoforms in tumour inflammation. First, we found that the AMPKα2 deficiency exacerbated the liver injury and recruitment of macrophages. Meanwhile, although compensatory expression of AMPKα1 was not significant after AMPKα2 knockout, AMPKα1 phosphorylation was elevated in remnant liver in AMPKα2 knockout mice, which was positively associated with the enhanced energy deprivation in the AMPKα2 deficient mice. Furthermore, the activated AMPKα1 in macrophage contributed to its polarizing to tumour‐associated phenotype. Thus, the enhanced tumour‐associated inflammation and activation of AMPKα1 in the AMPKα2 deficient mice may exacerbate the tumour development by affecting the tumour inflammatory microenvironment. Our study suggests that the two isoforms of AMPKα, AMPKα1 and AMPKα2 play different roles in controlling tumour development.