MAPK4 silencing in gastric cancer drives liver metastasis by positive feedback between cancer cells and macrophages.
MAPK4 silencing in gastric cancer drives liver metastasis by positive feedback between cancer cells and macrophages.
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DOI：
10.1038/s12276-023-00946-w
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发表时间：
2023-03
影响因子：
12.8
通讯作者：
Zhou, Tianhua
中科院分区：
文献类型：
--
作者：
Li, Shuang;Guo, Dongyang;Sun, Qiang;Zhang, Lu;Cui, Yun;Liu, Min;Ma, Xixi;Liu, Yiman;Cui, Wenyu;Sun, Leimin;Teng, Lisong;Wang, Liangjing;Lin, Aifu;Liu, Wei;Zhuo, Wei;Zhou, Tianhua
肝转移是胃癌患者死亡的主要原因，但其潜在机制尚不清楚。通过结合体内筛选和转录组分析，然后进行定量RT-PCR和组织芯片分析，我们发现，丝裂原活化蛋白激酶4（MAPK 4）在胃癌患者组织中表达下调与肝转移和预后不良显著相关。在原位小鼠模型中，胃癌细胞中MAPK 4的敲低促进肝转移。胃癌细胞中的MAPK 4缺失诱导巨噬细胞迁移抑制因子（MIF）分泌至原位异种移植肿瘤中的肿瘤相关巨噬细胞（TAM）。此外，TAMs激活胃癌细胞的上皮-间充质转化以抑制MAPK 4表达，从而进一步增加MIF分泌，使TAMs极化。综上所述，我们的研究结果表明，癌细胞和巨噬细胞之间的MAPK 4沉默介导的一个以前未描述的正反馈回路，促进胃癌肝转移。关键细胞控制基因的活性降低介导胃癌细胞和称为巨噬细胞的免疫系统细胞之间的相互作用，使癌症扩散到肝脏。癌细胞迁移到肝脏是胃癌患者死亡的主要原因，但驱动这一过程的机制尚不清楚。由杭州浙江大学医学院的Tianhua Zhou和Wei Zhuo领导的中国研究人员研究了患者癌细胞中基因及其相应蛋白质的活性，并分析了胃癌小鼠模型中的基因活性。他们发现，产生一种名为MAPK 4的蛋白质的基因在癌细胞中显着减少。这使得细胞与巨噬细胞相互作用，促进它们扩散到肝脏。
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. Reduced activity of a key cell control gene mediates an interaction between gastric cancer cells and immune system cells called macrophages that allows the cancer to spread to the liver. Cancer cells migrating to the liver is a major cause of death for gastric cancer patients, but the mechanisms driving this process have been unclear. Researchers in China led by Tianhua Zhou and Wei Zhuo at Zhejiang University School of Medicine, Hangzhou, studied the activity of genes and their corresponding proteins in patients’ cancer cells, and analyzed gene activity in mouse models of gastric cancer. They found that the gene that generates a protein called MAPK4 is significantly reduced in the cancer cells. This allows the cells to interact with macrophages, promoting their spread to the liver.
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