Long non-coding RNA PVT1 encapsulated in bone marrow mesenchymal stem cell-derived exosomes promotes osteosarcoma growth and metastasis by stabilizing ERG and sponging miR-183-5p

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.

Use of Stem Cell Extracellular Vesicles as a “Holistic” Approach to CNS Repair

“…Interestingly, EVs derived from PVT1 knockdown cells negated these effects, thereby highlighting their potential therapeutic application for osteosarcoma. In addition to the direct interaction between PVT1 and ERG, it was confirmed that PVT1 also promoted ERG expression through the sponging of miR-183-5p (Zhao W. et al, 2019).…”

“…Similarly, Zhao W. et al (2019) found that the lncRNA PVT1 was enriched in EVs from BM-MSCs. EV-associated PVT1 increased/stabilized the expression of oncogenic protein ERG, which correlated to increased proliferation and migration of osteosarcoma cells in vitro and promoted tumor growth and metastasis in vivo.…”

Extracellular vesicle long non–coding RNA‐mediated crosstalk in the tumor microenvironment: Tiny molecules, huge roles

“…sEV LINC00461 positively modulates BCL‐2 expression by competitively binding to miR‐15a/miR‐16, leading to enhanced cellular proliferation and reduced apoptosis of MM cells 37 . Zhao et al indicated that lncRNA PVT1 could be encapsulated and transferred to osteosarcoma cells in bone marrow MSC‐derived sEV, which promotes tumor growth and metastasis by inhibiting the ubiquitination of ERG protein and sponging miR‐183‐5p 38 …”

The Roles of ceRNAs-Mediated Autophagy in Cancer Chemoresistance and Metastasis

“…Exosomes, extracellular vesicles containing ncRNAs and proteins, are crucial for cellular communication in tumorigenesis in autocrine, paracrine, and endocrine manners [ 147 ]. lncRNAs such as PVT1 and UCA1 can be packaged into exosomes to link the crosstalk between stromal cells and tumor cells partly through autophagy regulation, thereby contributing to pre-metastasis niche formation [ 148 , 149 ]. PVT1 promoted tumor cell metastasis by upregulating autophagy.…”

“…PVT1 promoted tumor cell metastasis by upregulating autophagy. Moreover, PVT1 was encapsulated into bone marrow mesenchymal stem cells (BMSCs)-derived exosomes and promoted osteosarcoma cell proliferation and migration [ 148 ]. The elevated UCA1 upregulated ATG7 in bladder cancers by sponging miR-582-5p [ 62 ].…”