Interferon Beta (IFN-beta)-Modified Bone Marrow Mesenchymal Stem Cells (BMSC) Impede Metastatic Tropism of Prostate Cancer via Modulating Transforming Growth Factor-Beta/Smads (TGF-Beta/Smads) Pathway

The study of Bone marrow mesenchymal stem cells (BMSCs)-based treatment is still unmet needs topic in recent years, especially focusing on the therapeutic effects of genetically modified BMSCs. IFN-beta acts as a critical mediator in the occurrence and progress of prostate cancer. Additionally, its related signal transduction pathways affect malignancies. This study aims to discussion the mechanism of IFN-beta-modified BMSCs in impeding the metastatic tropism of prostate cancer. A total of 40 male mice (SPF) with a clean grade were randomized into 4 groups (10 mice per group) as follows: control group, BMSCs group, IFN-beta modified BMSCs group and TGF-beta/Smads inhibitor group. The following indicators were investigated: the expression level of IFN-beta in IFN-beta-modified BMSCs, in vitro metastatic tropism of prostate cancer cells, quantification of TGF-beta and Smads protein, along with the targeting of IFN-beta and TGF-beta/Smads. The expression of IFN-beta level was significantly increased denoted in the modified BMSCs (1.82 +/- 0.42) in comparison with those unmodified BMSCs (P < 0.05). After 48- and 72-hour culture, the proportion of migrating cells in the IFN-beta-modified BMSCs group was significantly decreased than those in other groups (P < 0.05). Meanwhile, cells in the TGF-beta/Smads inhibitor group exhibited a significantly weaker tendency to migrate in comparison with those in the control group and BMSCs group, but still showed more migrating cells compared to cells in the IFN-beta-modified BMSCs group (P < 0.05). Moreover, a significant reduction of migrated cells was denoted in the BMSCs group after 48- and 72-hour culture in comparison with the control group (P < 0.05). The weakest expression of TGF-beta/Smads proteins was denoted in the IFN-beta-modified BMSCs group, followed by the TGF-beta/Smads inhibitor group, BMSCs group and control group (P < 0.05). The TGF-beta/Smads inhibitor group exhibited significantly decreased levels of TGF-beta/Smads proteins in comparison with the control group and BMSCs group (P < 0.05). Moreover, a significant decline of TGF-beta/Smads proteins was denoted in the BMSCs group in comparison with the control group (P < 0.05). The IFN-beta gene was incubated separately with wild-type and mutant plasmids in the dual-luciferase reporter gene assay. The results indicated that the expression of IFN-beta was stronger in the mutant plasmids (P < 0.05) IFN-beta-modified BMSCs can boost the entrance of IFN-beta into prostate cancer cells, thereby enhancing their expression of IFN-beta, which resulted in the expression impediment of TGF-beta/Smads signals, leading to an inhibited metastatic tropism of prostate cancer cells. Its mechanism was mainly related to the TGF-beta/Smads signal transduction pathway.