Exosomes derived from gastric cancer cells trigger M2 polarization of hepatic Kupffer cells via miRNA to promote the formation of pre-metastatic hepatic niche
10.3760/cma.j.cn112309-20240629-00237
- VernacularTitle:胃癌细胞外泌体经miRNA触发肝Kupffer细胞M2型极化以促进肝转移前生态位的形成
- Author:
Xuan ZHANG
1
;
Wei LIU
;
Haixiao FU
;
Tengteng LI
;
Hao LIU
;
Wei FU
;
Kai WANG
Author Information
1. 徐州医科大学附属医院胃肠外科，徐州 221002
- Keywords:
Gastric cancer;
Exosomes;
Kupffer cells;
M2-like polarization;
Pre-metastatic liver niche
- From:
Chinese Journal of Microbiology and Immunology
2024;44(9):762-770
- CountryChina
- Language:Chinese
-
Abstract:
Objective:To investigate the influence of the interaction between gastric cancer (GC) cell-derived exosomes and hepatic Kupffer cells on GC with liver metastasis and analyze the potential mechanism.Methods:Cells with high hepatic metastatic potential (MKN 45-HL) were constructed from a parental GC cell line (MKN 45) using a nude mouse model and methods of viral transfection and flow sorting. Exosomes were collected using ultra-centrifugation and characterized by electron microscopy, nanoparticle tracking system and Western blot. A nude mouse model of liver metastasis induced by GC cell-derived exosomes was constructed, and the development of liver metastases was monitored by live imaging. The regulatory effects of GC cell-derived exosomes on macrophage polarization were assessed by cell culture, qRT-PCR, and immunofluorescence staining. Using the omics analysis of exosomal miRNA and qRT-PCR, the molecular targets by which exosomes specifically promoting macrophage M2 polarization were screened and validated.Results:GC cell-derived exosomes were mainly concentrated in the liver, most of which were ingested by intrahepatic macrophages, and could promote macrophages to M2 polarization in both in vitro culture and nude mice. Both groups of mice trained with MKN 45 and MKN 45-HL exosomes showed obvious liver metastases after mouse forestomach carcinoma (MFC) cells injection through the spleen, and MKN 45-HL exosomes showed a much stronger ability to promote hepatic macrophage M2 polarization and liver metastasis of MFC cells. Moreover, the miRNA omics analysis revealed a lot of differentially expressed miRNAs between MKN 45-derived and MKN 45-HL-derived exosomes. The expression of miR-519a-3p increased significantly in the exosomes derived from MKN 45-HL cell line and the clinical serum of GC patients with liver metastasis. It was found that miR-519a-3p could be internalized by macrophages through exosomes delivery. Furthermore, the miR-519a-3p in exosomes from patient′s serum had a predictive value for GC with liver metastasis and was closely associated with the prognosis of GC patients with liver metastasis. Conclusions:GC cell-derived exosomes trigger M2-like polarization of hepatic Kupffer cells via miR-519a-3p, thus promoting the progression of liver metastasis in GC and playing a critical role in shaping the pre-metastatic liver niche in gastric cancer. This study provides a new perspective on the mechanism of GC with liver metastasis and reveal potential targets for future therapeutic strategies.
