Abstract
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.
Highlights
Prostate cancer (PCa) is a common malignant tumour of the male urogenital system, the second leading cause of cancer mortality in men worldwide and a significant cause of death in elderly men [1, 2]
We demonstrate that extracts obtained from cell culture supernatants contained exosomes and that miR-141-3p levels were significantly higher in MDA prostate cancer (PCa) 2b cell exosomes
We found that miR-141-3p released from PCa cells could be transferred to osteoblasts and promote osteoblast activity, which was conducive to the formation of a bone-metastasis microenvironment
Summary
Prostate cancer (PCa) is a common malignant tumour of the male urogenital system, the second leading cause of cancer mortality in men worldwide and a significant cause of death in elderly men [1, 2]. Studies have shown that PCa cells interact with the microenvironment of bone metastases through a variety of cytokines, extracellular matrix components and intercellular signalling networks, which play an important role in the occurrence and development www.impactjournals.com/oncotarget of bone metastases [5, 6]. Clarifying the mechanism by which cancer cells interact with the bone metastatic microenvironment to establish PCa bone metastases is essential for developing disease prevention and control strategies and improving disease prognosis. Cancer cells have been shown to release a variety of exosomes that contain miRNAs and reach metastatic loci prior to cancer cells, stimulating the transfer of the cancer microenvironment and thereby promoting tumour metastasis [9]. Our previous work demonstrated that exosomal miR-141-3p is upregulated in the serum of metastatic PCa patients, which is related to bone metastasis [13]. The role and regulatory mechanism of miR-141-3p in the bone metastasis microenvironment remains poorly understood
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