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KMID : 0620920230550020457
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Experimental & Molecular Medicine
2023 Volume.55 No. 2 p.457 ~ p.469
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MAPK4 silencing in gastric cancer drives liver metastasis by positive feedback between cancer cells and macrophages
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Shuang Li
Dongyang Guo
Qiang Sun
Moon Hye-Jin
Yun Cui
Min Liu
Xixi Ma
Yiman Liu
Wenyu Cui
Leimin Sun
Cancer Center
Liangjing Wang
Aifu Lin
Wei Liu
Wei Zhuo
Tianhua Zhou
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Abstract
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Liver metastasis is a major cause of death in gastric cancer patients, but the underlying mechanisms are poorly understood. Through a combination of in vivo screening and transcriptome profiling followed by quantitative RT-PCR and tissue array analyses, we found that mitogen-activated protein kinase 4 (MAPK4) downregulation in gastric cancer tissues from patients is significantly associated with liver metastasis and poor prognosis. The knockdown of MAPK4 in gastric cancer cells promotes liver metastasis in orthotopic mouse models. MAPK4 depletion in gastric cancer cells induces the secretion of macrophage migration inhibitory factor (MIF) to polarize tumor-associated macrophages (TAMs) in orthotopic xenograft tumors. Moreover, TAMs activate epithelial?mesenchymal transition of gastric cancer cells to suppress MAPK4 expression, which further increases MIF secretion to polarize TAMs. Taken together, our results suggest a previously undescribed positive feedback loop between cancer cells and macrophages mediated by MAPK4 silencing that facilitates gastric cancer liver metastasis.
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KEYWORD
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Cancer microenvironment, Gastric cancer, Metastasis
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