ABSTRACT
The lung is one of the most common sites for cancer metastasis. Collagens in the lung provide a permissive microenvironment that supports the colonization and outgrowth of disseminated tumor cells. Therefore, down-regulating the production of collagens may contribute to the inhibition of lung metastasis. It has been suggested that miR-29 exhibits effective anti-fibrotic activity by negatively regulating the expression of collagens. Indeed, our clinical lung tumor data shows that miR-29a-3p expression negatively correlates with collagen I expression in lung tumors and positively correlates with patients' outcomes. However, suitable carriers need to be selected to deliver this therapeutic miRNA to the lungs. In this study, we found that the chemotherapy drug cisplatin facilitated miR-29a-3p accumulation in the exosomes of lung tumor cells, and this type of exosomes exhibited a specific lung-targeting effect and promising collagen down-regulation. To scale up the preparation and simplify the delivery system, we designed a lung-targeting liposomal nanovesicle (by adjusting the molar ratio of DOTAP/cholesterol-miRNAs to 4:1) to carry miR-29a-3p and mimic the exosomes. This liposomal nanovesicle delivery system significantly down-regulated collagen I secretion by lung fibroblasts in vivo, thus alleviating the establishment of a pro-metastatic environment for circulating lung tumor cells.
ABSTRACT
Objective To investigate the regulation of mesenchymal stem cells (MSCs) on the expression of tumor necrosis factor-α-induced protein 8-like 2 (TNFAIP8L2, TIPE2) in the peripheral blood-derived macrophages of systemic lupus erythematosus (SLE) patients. Methods The expression of TIPE2 mRNA in peripheral blood mononuclear cells (PBMCs) and macrophages from SLE patients were detected by Quantitative polymerase chain reaction (qPCR). The TIPE2 protein levels in SLE PBMCs and peripheral blood-derived macrophages were detected by western blot, flow cytometry and immunofluorescence staining, respec-tively. Data were analyzed by t test and Spearman correlation analysis. Results The TIPE2 mRNA expres-sion in PBMCs of SLE patients was significantly lower than that of healthy controls [(0.41 ±0.14) vs (1.06±0.39), t=5.376, P<0.01], as well as the TIPE2 protein level [(0.40 ±0.21) vs (1.09 ±0.26), t=2.963, P<0.05]. The expression of TIPE2 mRNA in peripheral blood-derived macrophages from SLE patients was significantly decreased [(0.56±0.24) vs (1.07±0.38), t=5.203, P<0.01). Moreover, TIPE2 mRNA level of peripheral blood-derived macrophages was negatively correlated with systemic lupus erythematosus disease activity index (SLEDAI) score (r=-0.60, P<0.01), 24-hour urinary protein (r=-0.46, P<0.05) and erythrocyte sedimentation rate (r=-0.46, P<0.05) in SLE patients. The percentage of TIPE2+cells in peripheral blood-derived macrophages (TIPE2+/CD14+)％ from SLE patients was significantly lower than that in healthy controls [(51.4 ±18.5)％ vs (82.4 ±7.5)％, t=2.679, P<0.05]. After 24 hours co-cultured with MSCs, the TIPE2 mRNA expression in SLE per-ipheral blood-derived macrophages was significantly increased [(2.2 ±0.7) vs (1.0 ±0.3), t=3.729, P<0.05). Immunofluorescence results showed the same increase of TIPE2 protein in SLE peripheral blood-derived macrophages [(0.112 ±0.020) vs (0.074 ±0.016), t=3.268, P<0.05]. Conclusion The TIPE2 level in peripheral blood-derived macrophages of SLE patients are decreased. MSCs upregulate the TIPE2 expression in vitro, suggesting that TIPE2 can be a new target for MSCs in the treatment of SLE.