Silencing SPP1 in M2 macrophages inhibits the progression of castration-resistant prostate cancer via the MMP9/TGFß1 axis.

Background: M2 macrophages can promote the progression of castration-resistant prostate cancer (CRPC), but the specific mechanism is still unclear. Therefore, we are preliminarily exploring the molecular mechanism by which M2 macrophages regulate the progression of CRPC. Methods: The genes positively correlated with CRPC and with the most significant differences in the GEO32269 dataset were obtained. Database and immunofluorescence experiments were used to validate the localization of secreted phosphoprotein 1 (SPP1) in localized prostate cancer (PCa), hormone-sensitive prostate cancer (HSPC), and CRPC tumor tissues. The function of SPP1 in M2 macrophages was verified through cell scratch, Transwell, and an orthotopic PCa model. PCa database and Western blot were used to verify the relationship between SPP1 and matrix metallopeptidase 9 (MMP9), as well as the ability of MMP9 in M2 macrophages to promote epithelial-mesenchymal transition (EMT) in PCa cells. Results: The primary localization of SPP1 in prostate and CRPC tissues is in macrophages. Silencing SPP1 expression in M2 macrophages promotes their polarization towards the M1 phenotype and significantly inhibits the malignant progression of PCa in vitro and in vivo. SPP1 promotes the expression of MMP9 through the PI3K/AKT signaling pathway in M2 macrophages. Furthermore, MMP9 enhances the EMT and migratory capabilities of PC3 cells by activating the TGFß signaling pathway. Conclusions: We have found that the high expression of SPP1 in M2 macrophages promotes the progression of CRPC through cell-cell interactions. These findings can contribute to the development of novel therapeutic approaches for combating this deadly disease.

Epithelial cells derived exosomal miR-203a-3p facilitates stromal inflammation of type IIIA chronic prostatitis/chronic pelvic pain syndrome by targeting DUSP5 and increasing MCP-1 generation.

Increased proinflammatory cytokines and infiltration of inflammatory cells in the stroma are important pathological features of type IIIA chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS-A), and the interaction between stromal cells and other cells in the inflammatory microenvironment is closely related to the inflammatory process of CP/CPPS-A. However, the interaction between stromal and epithelial cells remains unclear. In this study, inflammatory prostate epithelial cells (PECs) released miR-203a-3p-rich exosomes and facilitated prostate stromal cells (PSCs) inflammation by upregulating MCP-1 expression. Mechanistically, DUSP5 was identified as a novel target gene of miR-203a-3p and regulated PSCs inflammation through the ERK1/2/MCP-1 signaling pathway. Meanwhile, the effect of exosomes derived from prostatic fluids of CP/CPPS-A patients was consistent with that of exosomes derived from inflammatory PECs. Importantly, we demonstrated that miR-203a-3p antagomirs-loaded exosomes derived from PECs targeted the prostate and alleviated prostatitis by inhibiting the DUSP5-ERK1/2 pathway. Collectively, our findings provide new insights into underlying the interaction between PECs and PSCs in CP/CPPS-A, providing a promising therapeutic strategy for CP/CPPS-A.

In vivo targeting capacities of different nanoparticles to prostate tissues based on a mouse model of chronic bacterial prostatitis.

Chronic bacterial prostatitis usually occurs in men and seriously affects the quality of life of patients. The efficacy of chronic bacterial prostatitis treatment is limited by the difficulty for free drugs (e.g., antibiotics) to penetrate the prostate epithelium and target inflammatory tissues. The advent of nanotechnology offers the possibility to address this issue, such as the development of targeted nanoparticle delivery strategies that may overcome these important limitations. The physicochemical properties of nanoparticles, such as particle size, shape and surface modification ligands, determine their targeting effectiveness. In this study, nanoparticles with different physicochemical properties were prepared to explore and confirm their targeting capacities to inflammatory prostate tissues of chronic bacterial prostatitis, focusing on the effects of size and different modification ligands on the targeting performance. In vivo and ex vivo imaging results verified that folic acid-modified nanoparticles with a particle size of 180-190 nm via tail intravenous injection had the optimal targeting efficiency to prostate tissues. Our results provide an experimental basis and reference value for targeted therapy of prostate-related diseases with nanotechnology in the future.