Identification of Urinary Exosomal miRNAs for the Non-Invasive Diagnosis of Prostate Cancer.

BACKGROUND: Novel and non-invasive biomarkers with higher sensitivity and specificity for the diagnosis of prostate cancer (PCa) is urgently needed. In this study, we used next-generation sequencing (NGS) to characterize the genome-wide exosomal miRNA expression profiling in urine specimens and explored the diagnostic potential of urinary exosomal miRNAs for PCa. METHODS: Urinary exosomal microRNA expression profiling was performed by next-generation sequencing (NGS) and then validated by quantitative real-time PCR. RESULTS: Significant downregulation of urinary exosomal miR-375 was observed in PCa patients compared with healthy controls, while the expression levels of urinary exosomal miR-451a, miR-486-3p and miR-486-5p were found to be significantly up-regulated in the PCa patients. Furthermore, the expression level of urinary exosomal miR-375 showed a significant correlation with the clinical T-stage and bone metastasis of patients with PCa (P<0.05). Receiver operator characteristic curve demonstrated that the urinary exosomal miR-375, miR-451a, miR-486-3p and miR-486-5p levels can be used to differentiate PCa patients from healthy controls, with area under the curves (AUCs) of 0.788, 0.757, 0.704 and 0.796, respectively. The urinary exosomal miR-375 was found to be superior in discriminating between localized and metastatic PCa with an AUC of 0.806. Moreover, PCa patients can be distinguished from patients with benign prostatic hyperplasia by using a panel combining urinary exosomal miR-375 and miR-451a with an AUC of 0.726. CONCLUSION: These findings demonstrate that the urinary exosomal miRNAs can serve as novel and non-invasive biomarkers for diagnosing and predicting the progression of PCa.

Exosomal miR-141-3p regulates osteoblast activity to promote the osteoblastic metastasis of prostate cancer.

Exosomes from cancer cells, which contain microRNA and reach metastasis loci prior to cancer cells, stimulate the formation of a metastatic microenvironment. Previous studies have shown that exosomal miR-141-3p is associated with metastatic prostate cancer (PCa). However, the role and regulatory mechanism of miR-141-3p in the microenvironment of bone metastases require further study. In this study, we performed a series of experiments in vivo and in vitro to determine whether exosomal miR-141-3p from MDA PCa 2b cells regulates osteoblast activity to promote osteoblastic metastasis. We demonstrate that extracts obtained from cell culture supernatants contained exosomes and that miR-141-3p levels were significantly higher in MDA PCa 2b cell exosomes. Via confocal imaging, numerous MDA PCa 2b exosomes were observed to enter osteoblasts, and miR-141-3p was transferred to osteoblasts through MDA PCa 2b exosomes in vitro. Exosomal miR-141-3p from MDA PCa 2b promoted osteoblast activity and increased osteoprotegerin OPG expression. miR-141-3p suppressed the protein levels of the target gene DLC1, indicating its functional significance in activating the p38MAPK pathway. In animal experiments, exosomal miR-141-3p had bone-target specificity and promoted osteoblast activity. Mice injected with miR-141-3p-mimics exosomes developed apparent osteoblastic bone metastasis. Exosomal miR-141-3p from MDA PCa 2b cells promoted osteoblast activity and regulated the microenvironment of bone metastases, which plays an important role in the formation of bone metastases and osteogenesis damage in PCa. Clarifying the specific mechanism of bone metastasis will help generate new possibilities for the treatment of PCa.