The effect of miR-506 on the tumor associated macrophages and tumor microenvironment of pancreatic ductal adenocarcinoma / 中华肝胆外科杂志

ABSTRACT

Objective:To explore the effect of miR-506 on the tumor associated macrophage (TAM) and tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC).Methods:Panc02 cells were used to establish in situ tumorigenesis mouse model. Tumor bearing C57BL/6 mice were divided into miR-ctrl C57 group and miR-506 C57 group, with 15 mice in each group. miR-ctrl or miR-506 coated with DOPC liposomes (miR-ctrl/DOPC or miR-506/DOPC) were injected intraperitoneally. The tumor weight and volume were measured, the changes of tumor infiltrating immune cells were detected by flow cytometry and the survival time of mice was monitored. To eliminate the influence of immune system, tumor bearing nude mice were divided into miR-ctrl nude group and mir-506 nude group, with 5 mice in each group. miR-ctrl/DOPC or miR-506/DOPC were injected intraperitoneally. To eliminate the influence of macrophages, tumor bearing C57BL/6 mice were randomly divided into control group and macrophage clearance group and injected intraperitoneally with PBS or clodronate liposome (Clo), with 10 mice in each group. Then each group was randomly divided into two groups (miR-ctrl PBS group and miR-506 PBS group, miR-ctrl Clo group and miR-506 Clo group), miR-ctrl PBS group and miR-ctrl Clo group were injected with miR-ctrl/DOPC via intraperitoneal injection, miR-506 PBS group and miR-506 Clo group were injected with miR-506/DOPC. Results:In C57BL/6 mice model, the tumor volume (1.04±0.23)×10 3 mm 3 and tumor weight (0.51±0.10)g of miR-506 C57 group was lower than those in miR-ctrl C57 group (1.92±0.34)×10 3 mm 3 and (0.99±0.19) g, the overall survival of miR-506 C57 group was longer than that of miR-ctrl C57 group. The ratio of M2/M1 in miR-506 C57 group (1.19±0.46) was lower than that in miR-ctrl C57 group (2.85±0.40). In BALB/C nude mice model, the tumor volume and tumor weight showed no significant difference between miR-506 nude group and miR-ctrl nude group. Compared with the miR-ctrl PBS group, the proportion of regulatory T cells decreased [(4.70±1.86)% vs. (12.00±2.24)%], the proportion of cytotoxic T cells increased [(10.54±1.89)% vs. (4.54±1.25)%], the proportion of apoptotic cytotoxic T cells decreased [(14.00±4.00)% vs. (26.80±4.27)%] and the concentration of IFN-γ increased in miR-506 PBS group [(89.60±14.69) vs. (28.00±13.69) ng/g]. However, after clearance of macrophages by Clo, there was no significant difference in the above indexes between mir-506 Clo group and miR-ctrl Clo group. Conclusion:MiR-506 inhibits the progression of PDAC and reverses its immunosuppressive TME in a macrophage dependent manner.