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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Background: Malignant biliary obstruction was typically diagnosed at an advanced stage due to painless jaundice. Stent placement is the therapy of choice in this set of patients. Radiofrequency ablation is an ablative therapy which has been well recognized for treating malignant biliary strictures. This meta-analysis aims to help to better understand the safety and efficacy of biliary Radiofrequency ablation combined with stent placement. Methods: Five databases (PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of Science, and China National Knowledge Infrastructure) were searched for randomized controlled trials and observational studies up to April 2020. Results: The mean difference in survival time was 54.87 days (95% confidence interval CI, 34.6-75.14), meaning patients performed with radiofrequency ablation benefit more. Reconstructed Kaplan-Meier data showed improved survival in joint intervention with RFA (hazard ratio, 1.39; 95%CI, 1.34-1.75; P < .001). However, no survival benefit was observed in the extrahepatic distal cholangiocarcinoma. With regard to patency time, the mean difference was 42.88 days (95%CI, 34.02-51.37). Reconstructed Kaplan-Meier data showed improved survival in the radiofrequency ablation treated group (hazard ratio, 1.629; 95%CI, 1.35-1.96; P < .001). Concerning postoperative complications such as abdominal pain, cholangitis and pancreatitis, our analysis did not show a significant difference between the radiofrequency ablation treatment group and the controls. Conclusion: Radiofrequency ablation plus stent resulted in improved survival and stent patency, with longer median survival and patency time than stent alone.