Abstract
BackgroundRecent studies have suggested a crucial role of mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) in ovarian cancer treatment. We, therefore, set out to explore the mechanism through which MSC-derived EVs delivered microRNA-424 (miR-424) to influence the development of ovarian cancer.MethodsBioinformatics analyses were first performed to screen ovarian cancer-related differentially expressed genes and to predict regulatory miRNAs. Then, dual-luciferase reporter gene assay was carried out to verify the relationship between miR-424 and MYB. Subsequently, the characterized MSCs and isolated EVs were co-cultured with ovarian cancer cells, followed by determination of the expression patterns of miR-424, MYB, vascular endothelial growth factor (VEGF), and VEGF receptor (VEGFR), respectively. In addition, the effects of EVs-delivered miR-424 on the proliferation, migration, invasion and tube formation of ovarian cancer cells were assessed using gain- and loss-of-function approaches. Lastly, tumor xenograft was induced in nude mice to illustrate the influence of EVs-loaded miR-424 on ovarian cancer in vivo.ResultsOur data exhibited that MYB was highly-expressed and miR-424 was poorly-expressed in ovarian cancer. More importantly, MYB was identified as a target gene of miR-424. Additionally, the transfer of miR-424 by MSC-derived EVs was found to repress the proliferation, migration, and invasion of ovarian cancer cells, with a reduction in the expressions of VEGF and VEGFR. Furthermore, MSC-derived EVs over-expressing miR-424 could inhibit the proliferation, migration, and tube formation of human umbilical vein endothelial cells, and also suppressed tumorigenesis and angiogenesis of ovarian tumors in vivo.ConclusionCollectively, our findings indicate that MSC-derived EVs transfer miR-424 to down-regulate MYB, which ultimately led to the inhibition of the tumorigenesis and angiogenesis of ovarian cancer. Hence, this study offers a potential prognostic marker and a therapeutic target for ovarian cancer.
Highlights
Recent studies have suggested a crucial role of mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) in ovarian cancer treatment
Results from the protein–protein interaction (PPI) network revealed that the KIT, TOP2A, and MYB genes exhibited a higher correlation with other genes, and were likely to affect the development of ovarian cancer
The heat map for the expression patterns of the first 150 differentially expressed genes (DEGs) in GSE4122 was plotted (Fig. 1c), which revealed that TOP2A and MYB were highly-expressed in ovarian cancer
Summary
Recent studies have suggested a crucial role of mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) in ovarian cancer treatment. Mesenchymal stem cells (MSCs) have surfaced as promising candidates for treating various diseases, and MSCs hold significant importance in ovarian cancer therapeutics [4, 5]. The hard-done work of our peers has highlighted the therapeutics importance of MSC-derived extracellular vesicles (EVs) [6], the promising role of EVs in the diagnosis and treatment of ovarian cancer [7]. A specific miRNA, the miR-424 is known to suppress the cell migration and proliferation of ovarian cancer [11], and further confers a suppressive effect on malignant phenotypes in ovarian clear cells through the down-regulation of doublecortin-like kinase 1 [12]. It can be speculated that miR-424 may participate in the pathogenesis and development of ovarian cancer
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