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

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.

Primary prostate cancer educates bone stroma through exosomal pyruvate kinase M2 to promote bone metastasis

“…In terms of PCa, there are several studies regarding the potential of serum and urine exosomes as biomarkers (Valentino et al, 2017;Wani et al, 2017;Fujita and Nonomura, 2018;Lee et al, 2018;Panigrahi et al, 2018;Wang et al, 2018); however, there are limited functional studies that delineate if exosomes mechanistically impact PCa metastasis. In one study, exosomes containing miR-141-3p were shown to target osteoblasts and increase osteoblast activity (Ye et al, 2017). Although, the authors concluded in that study that exosome miR-141-3p enhanced osteoblastic metastasis, in that study, they injected mimic miR-141-3p miRNAs into the cancer cells that were then injected into the mice intratibially; thus, one may not conclude that the exosomes achieved their effect through altering the microenvironment or that there was any impact on tumor seeding.…”

Retracted: Alpinumisoflavone Inhibits Tumor Growth and Metastasis in Papillary Thyroid Cancer via Upregulating miR‐141‐3p

“…In contrast, numerous studies have also revealed that miR‐141‐3p exerts regulatory role in tumorgenesis and progression by serving as an oncogene. For example, exosomal miR‐141‐3p promotes the bone metastasis of prostate cancer through modulating osteoblast activity (Ye et al, ). Similarly, another study also confirmed that miR‐141‐3p was aberrantly upregulated in ESSC and subsequently promoted cancer progression and metastasis through activating AKT/PI3K pathway (Ishibashi et al, ).…”

Extracellular vesicles: Toward a clinical application in urological cancer treatment

“…They found that secreted miR‐141‐3p reduced levels of DLC1 in osteoblasts and activated the p38MAPK pathway, promoting osteoblast proliferation and OPG/RANKL expression. In addition, they also found that EVs derived from PCa had bone‐target specificity and promoted osteoblastic bone metastasis in vivo . Karlsson et al .…”

“…In addition, they also found that EVs derived from PCa had bone-target specificity and promoted osteoblastic bone metastasis in vivo. 111 Karlsson et al reported that EVs derived from the murine PCa cell line, TRAMP-C1, decreased fusion and differentiation of murine osteoclast precursors to mature multinucleated osteoclasts. Although the molecular mechanism underlying this phenotype was not shown, they suggested that EVs derived from PCa also regulated osteoclast differentiation in bone metastatic sites.…”