Abstract
Exosomes secreted by bone marrow mesenchymal stem cells (BMSCs) promote osteosarcoma cell proliferation and migration, while the underlying mechanism remains unknown. Since the long non-coding RNA PVT1 has been reported to be upregulated in osteosarcoma cells and contributes to its growth and metastasis, we aim to investigate whether BMSC-derived exosomes promote osteosarcoma growth and metastasis via transporting PVT1 into osteosarcoma cells. The PVT1 expression in BMSC-derived exosomes was markedly higher than that in osteosarcoma cell-derived exosomes. The co-culturing of BMSC-derived exosomes and osteosarcoma cells (Saos-2, MG-63, and MNNG/HOS cell lines) significantly raised PVT1 expression of osteosarcoma cells. The direct binding between PVT1 and the oncogenic protein ERG was confirmed using RNA immunoprecipitation and RNA pull-down assays, and the transported PVT1 promotes osteosarcoma cell proliferation and migration via inhibiting degradation and ubiquitination of ERG. PVT1 also increased ERG expression through sponging miR-183-5p. In summary, our findings indicated that BMSC-derived exosomes encapsulate PVTl and transport it into osteosarcoma cells, and the transported PVT1 promotes tumor growth and metastasis by inhibiting ubiquitination and promoting expression of ERG in osteosarcoma cells. These data provide a novel insight into the mechanism of BMSC-derived exosomes in affecting osteosarcoma progression.
Highlights
Osteosarcoma is a malignant bone tumor with the highest morbidity in children and adolescents, and is clinically localized in the metaphysis of long bones [1]
The different expressions of plasmacytoma variant translocation 1 (PVT1) were compared between BMSCEXO and MNNG-EXO using Quantitative real-time PCR (qRT-PCR), and the result showed an elevator of PVT1 expression in BMSCEXO (Figure 1C), suggesting that the upregulation of PVT1 in osteosarcoma cells may be derived from the transportation of Bone marrow mesenchymal stem cells (BMSCs)-EXO
We downregulated the expression of PVT1 in exosomes by interfering PVT1 in BMSCs (Figure 1E), the PVT1 expression in osteosarcoma cells showed a reduction after co-culturing with BMSC-EXOsi-PVT1 (Figure 1F)
Summary
Osteosarcoma is a malignant bone tumor with the highest morbidity in children and adolescents, and is clinically localized in the metaphysis of long bones [1]. The early metastasis and lung metastasis are commonly seen in osteosarcoma, causing the main mortality of osteosarcoma patients [2]. With the limited treatment of osteosarcoma, it desires better solution to deal with osteosarcoma. In recent years, growing researches have shown that the tumor microenvironment (TME) plays an important role in tumor progression [3, 4]. Bone marrow mesenchymal stem cells (BMSCs) are one of the major components in the TME of osteosarcoma and are corroborated to mediate proliferation and metastasis of tumor cells [5]. BMSCs exert their functions partly through secreting active substances, such as exosomes, to activate signal transduction pathways in osteosarcoma cells [6, 7]
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