PGRN -/- TAMs-derived exosomes inhibit breast cancer cell invasion and migration and its mechanism exploration
Shujun Yue 1 , Xiangsen Ye 1 , Ting Zhou 1 , Delu Gan 1 , Husun Qian 1 , Wenli Fang 1 , Mengli Yao 1 , Dian Zhang 1 , He Shi 1 , Tingmei Chen 2 Affiliations
- PMID: 33181174
- DOI: 10.1016/j.lfs.2020.118687
Breast cancer is one of the most malignant diseases world-wide and ranks the first among female cancers. Progranulin (PGRN) plays a carcinogenic role in breast cancer, but its mechanisms are not clear. In addition, there are few reports on the relationship between PGRN and tumor-associated macrophages (TAMs).
Aims: To investigate the effects of exosomes derived from PGRN-/- TAMs on invasion and migration of breast cancer cells.
Main methods: Mouse breast cancer xenograft model was constructed to explore the effect of PGRN-/- tumor environment (TME) on breast cancer. Flow cytometry was used to compare TAMs of wild type (WT) and PGRN-/- tumor tissue. Transwell assay, wound healing assay and western blot were used to explore the effect of WT and PGRN-/- TAMs and their exosomes on invasion, migration and epithelial-mesenchymal transition (EMT) of breast cancer cells. MicroRNA (miRNA) assay was used to find out the differentially expressed miRNA of negative control (NC) and siPGRN-TAMs exosomes. Quantitative PCR and luciferase report assay were used to explore the target gene.
Key findings: The lung metastasis of breast cancer of PGRN-/- mice was inhibited. PGRN-/- TAMs inhibited invasion, migration and EMT of breast cancer cells through their exosomes. MiR-5100 of PGRN-/- TAMs-derived exosomes was up-regulated, which might regulate expression of CXCL12, thereby inhibiting the CXCL12/CXCR4 axis, and ultimately inhibiting the invasion, migration and EMT of breast cancer cells.
Significance: Our study elucidates a new molecular mechanism of lung metastasis of breast cancer, so it may contribute to efficient prevention and therapeutic strategies.
Keywords: Breast cancer; Exosomes; PGRN; TAMs.