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Prostate cancer-derived small extracellular vesicles promote osteoclastogenesis and cancer-induced osteolysis via miR-152-3p delivery

ABSTRACT: Extracellular vesicles (EVs) play critical roles in regulating bone metastatic microenvironment through mediating intercellular communications. Here, we report a direct regulatory mode between tumor cells and osteoclasts in osteolytic metastasis of prostate cancer via vesicular miRNAs transfer. Combined analysis of miRNAs profiles both in tumor-derived small EVs (sEVs) and osteoclasts identified miR-152-3p as a potential osteolytic molecules. Further in vitro experiments showed that sEVs were enriched in miR-152-3p, which targets osteoclastogenic regulator MAFB. Blocking miR-152-3p in sEVs upregulated the expression of MAFB and impaired osteoclastogenesis in recipient osteoclasts. In vivo xenograft mouse model found that blocking of miR-152-3p in sEVs significantly rescued the loss of trabecular architecture, while systemic inhibition of miR-152-3p using antagomiR-152-3p reduced the osteolytic lesions of cortical bone while remaining the basic trabecular architecture. Together, our findings suggest that miR-152-3p carried by prostate cancer-derived sEVs deliver osteolytic signals from tumor cells to osteoclasts, facilitating osteolytic progression in bone metastasis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE161419 | GEO | 2021/02/24

REPOSITORIES: GEO

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Project description:Malignant germ-cell-tumours (GCTs) are characterised by microRNA (miRNA/miR-) dysregulation, with universal over-expression of miR-371~373 and miR-302/367 clusters regardless of patient age, tumour site, or subtype (seminoma/yolk-sac-tumour/embryonal carcinoma). These miRNAs are released into the bloodstream, presumed within extracellular-vesicles (EVs) and represent promising biomarkers. Here, we comprehensively examined the role of EVs, and their miRNA cargo, on (fibroblast/endothelial/macrophage) cells representative of the testicular GCT (TGCT) tumour microenvironment (TME). Small RNA next-generation-sequencing was performed on 34 samples, comprising representative malignant GCT cell lines/EVs and controls (testis fibroblast [Hs1.Tes] cell-line/EVs and testis/ovary samples). TME cells received TGCT co-culture, TGCT-derived EVs, and a miRNA overexpression system (miR-371a-OE) to assess functional relevance. TGCT cells secreted EVs into culture media. MiR-371~373 and miR-302/367 cluster miRNAs were overexpressed in all TGCT cells/subtypes compared with control cells and were highly abundant in TGCT-derived EVs, with miR-371a-3p/miR-371a-5p the most abundant. TGCT co-culture resulted in increased levels of miRNAs from the miR-371~373 and miR-302/367 clusters in TME (fibroblast) cells. Next, fluorescent labelling demonstrated TGCT-derived EVs were internalised by all TME (fibroblast/endothelial/macrophage) cells. TME (fibroblast/endothelial) cell treatment with EVs derived from different TGCT subtypes resulted in increased miR-371~373 and miR-302/367 miRNA levels, and other generic (eg, miR-205-5p/miR-148-3p) and subtype-specific (seminoma, eg, miR-203a-3p; yolk-sac-tumour, eg, miR-375-3p) miRNAs. MiR-371a-OE in TME cells resulted in increased collagen contraction (fibroblasts) and angiogenesis (endothelial cells), via direct mRNA downregulation and alteration of relevant pathways. TGCT cells communicate with nontumour stromal TME cells through release of EVs enriched in oncogenic miRNAs, potentially contributing to tumour progression.

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Prostate cancer-derived small extracellular vesicles promote osteoclastogenesis and cancer-induced osteolysis via miR-152-3p delivery

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