Cancer-derived exosomal miR-375 targets DIP2C and promotes osteoblastic metastasis and prostate cancer progression by regulating the Wnt signaling pathway.

Abstract

Bone metastasis is the most common complication responsible for most deaths in the advanced stages of prostate cancer (PCa). However, the exact mechanism of bone metastasis in PCa remains unelucidated. Herein, we explored the function and potential underlying mechanism of exosomal miR-375 in bone metastasis and tumor progression in PCa. This study revealed that miR-375 expression was markedly upregulated in advanced PCa with bone metastasis and metastatic PCa cell lines. Moreover, miR-375 showed high expression in PCa-derived exosomes and could be delivered to human mesenchymal stem cells (hMSCs) via exosomes. Mechanistically, miR-375 directly targeted DIP2C and upregulated the Wnt signaling pathway, thereby promoting osteoblastic differentiation in hMSCs. Furthermore, miR-375 promoted the proliferation, invasion, and migration of PCa cells in vitro and enhanced tumor progression and osteoblastic metastasis in vivo. Notably, the expression of miR-375, TCF-1, LEF-1, and β-catenin in was higher in PCa tissues with bone metastasis than in PCa tissues without bone metastasis and showed a continuous increase, whereas DIP2C, cyclin D1, and Axin2 showed an opposite expression pattern. In conclusion, our study suggests that cancer-derived exosomal miR-375 targets DIP2C, activates the Wnt signaling pathway, and promotes osteoblastic metastasis and PCa progression.