MAPK4 silencing in gastric cancer drives liver metastasis by positive feedback between cancer cells and macrophages.
Shuang LiDongyang GuoQiang SunLu ZhangYun CuiMin LiuXixi MaYiman LiuWenyu CuiLeimin SunLi Song TengLiang-Jing WangAifu LinWei LiuWei ZhuoTianhua ZhouPublished in: Experimental & molecular medicine (2023)
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.
Keyphrases
- signaling pathway
- poor prognosis
- epithelial mesenchymal transition
- pi k akt
- oxidative stress
- end stage renal disease
- ejection fraction
- newly diagnosed
- long non coding rna
- gene expression
- prognostic factors
- cell proliferation
- mouse model
- adipose tissue
- dna methylation
- patient reported outcomes
- transcription factor
- transforming growth factor
- binding protein