Abstract
Bone marrow mesenchymal stem cells (BMSCs) can boost osteosarcoma (OS) cell proliferation and invasion, yet the function of extracellular vesicles (EVs) derived from BMSCs on OS is scarcely known. This study is aimed at examining the role of BMSC-EVs in OS cells. BMSCs and BMSC-EVs were isolated and identified. The effect of EVs and EVs-si-NORAD on OS cell proliferation, invasion, migration, and angiogenesis was determined. Expressions of NORAD, miR-877-3p, and CREBBP were detected. The binding relationship among NORAD, miR-877-3p, and CREBBP was verified. The miR-877-3p inhibitor or pc-CREBBP was delivered into OS cells treated with EVs-si-NORAD for in vitro analysis. The nude mouse model of the subcutaneous tumor xenograft was established for in vivo analysis. BMSC-EVs promoted OS cell proliferation, invasion, migration, and angiogenesis. BMSC-EVs carried NORAD into OS cells and upregulated CREBBP by sponging miR-877-3p. miR-877-3p downregulation or CREBBP overexpression partly inverted the inhibitory effect of EVs by silencing NORAD on OS cell proliferation, invasion, migration, and angiogenesis. In vivo experiments validated that BMSC-EV-derived NORAD facilitated tumor growth by upregulating CREBBP via miR-877-3p. To conclude, BMSC-EV-derived NORAD facilitated OS cell proliferation, invasion, migration, and angiogenesis by modulating CREBBP via miR-877-3p, which may offer new insights into OS treatment.
Highlights
Osteosarcoma (OS) is one of the malignant tumors of bone with complex etiology and is common among adolescents and teenagers during fast growth in the metaphyseal of long bones, which accounts for 60% clinical incidence in all malignant tumors of bone in teenagers [1, 2]
Bone marrow mesenchymal stem cells (BMSCs)-extracellular vesicles (EVs) are capable of promoting OS cell proliferation by carrying long noncoding RNAs (lncRNAs) [29]
LncRNA noncoding RNA activated by DNA damage (NORAD) was found to be upregulated in OS cell lines and clinical samples [30]
Summary
Osteosarcoma (OS) is one of the malignant tumors of bone with complex etiology and is common among adolescents and teenagers during fast growth in the metaphyseal of long bones, which accounts for 60% clinical incidence in all malignant tumors of bone in teenagers [1, 2]. Due to the features of high malignancy and rapid growth, patients are generally diagnosed with an advanced OS that is accompanied by metastasis and low survival rates [3]. Tumor angiogenesis plays a significant part in the tumorigenesis and metastasis of OS [4]. Thereafter, it is imperative to study the pathogenesis of OS and explore the potential biomarkers and therapeutic targets for OS treatment. Alcian blue staining Count (a) CD29 P2 (97.94%) CD90 P2 (98.67%) (b)
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