Cancer-Derived Exosomal miR-199b-5p Inhibits Distant Metastases of Prostate Cancer by Counteracting the DDR1-MAPK/ERK-EMT Pathway

Metastasis remains a primary challenge in treating prostate cancer (PCa). In this study, we analyzed the transcriptomes of localized PCa and bone metastatic PCa patients derived plasma exosomes by using high-throughput RNA sequencing. We found that miR-199b-5p was down-regulation in plasma exosomes of bone metastatic PCa, primary PCa tissues of metastatic patients, as well as bone-related metastatic PCa cells. Over-expressed miR-199b-5p could significantly suppress the proliferation, migration, and metastatic behavior of PCa cells. Clinical data form Taylor dataset indicated that low miR-199b-5p expression level was dramatically correlated with high Gleason score, advanced pathological stage, positive metastasis, and biochemical recurrence of PCa patients. DDR1 (discoid domain receptor 1), the direct target of miR-199b-5p, was responsible for miR-199b-5p down-regulation mediated PCa progression. This process might associate with the activation of MAPK/ERK signaling and the development of EMT. The clinical data from our hospital, TCGA dataset, and GEO database collectively suggested a positive relationship between DDR1 expression and the poor prognosis of PCa. Collectively, exosomal miR-199b-5p-DDR1 axis might act as the potential metastatic diagnostic biomarkers for PCa and provide a new therapeutic strategy for metastatic PCa. Funding Statement: This work was supported by the grants from National Natural Science Foundation of China (No. 81372774, No. 81572537 for Zhigang Zhao), The Key Program of Natural Science Foundation of Guangdong Province (No. 2015A030311007 for Zhigang Zhao), Science and Technology Program of Guangzhou (No. 201607010376 for Zhigang Zhao), and The Major Program of Department of Guangdong Education (No. 2017KZDXM067 for Zhigang Zhao). Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: The present study was approved by the Human Study Ethics Committees of the First Affiliated Hospital of Guangzhou Medical University. All of the patients have signature informed consent. Human specimens were handled and made anonymous in adherence to the ethical and legal standards.