Abstract
Strategies targeted vascular endothelial growth factor (VEGF)-dependent osteosarcoma progression are limited although important progress has been made in illustrating the mechanisms. Here we identified circ_001621 as one of the significantly upregulated circular RNAs (circRNAs) by circRNAs microarrays. We found that patients with high circ_001621 expression had a shorter survival time. Moreover, we found several potential sponge micro RNAs (miRNA) of circ_001621 with Circular RNA Interactome database. Among the candidate sponge, we elucidated the association of circ_001621 and miR-578. In addition, we demonstrated that miR-578 targeted circ_001621 directly. Functionally, we set up the experimental system to investigate the effects of circ_001621/miR-578/VEGF interaction in vitro and in vivo. Results indicated circ_001621-promoted osteosarcoma proliferation and migration via attenuating the inhibition of cyclin-dependent kinase 4 (CDK4) and matrix metallopeptidase 9 (MMP9) by miR-578, respectively. Nude mice experiment was further performed to estimate the promotion of metastasis by circ_001621. The present study evaluated the mechanisms underlying circ_001621 enhanced osteosarcoma progression and provided novel therapeutic targets for advanced osteosarcoma.
Highlights
Osteosarcoma, emerging from mesenchymal cells, is a high-grade primary bone sarcoma and tends to occur in children and young adults
Serious side effects and limited response rates make the need for understanding the complex mechanisms involved in osteosarcoma initiation, progression, and metastasis urgently
Similar results were observed in U2OS cells (Fig. 2f, g). These results suggested that miR-578 targeted vascular endothelial growth factor (VEGF)
Summary
Osteosarcoma, emerging from mesenchymal cells, is a high-grade primary bone sarcoma and tends to occur in children and young adults. Despite the current regimens combining surgery, chemotherapy, and radiotherapy, the clinical outcome of advanced osteosarcoma is inadequate[1,2]. Numerous patients suffer from recurrence due to potential or existing distant metastasis. Additional strategies have been developed for patients with recurrent osteosarcoma, such as targeted therapies[3]. Serious side effects and limited response rates make the need for understanding the complex mechanisms involved in osteosarcoma initiation, progression, and metastasis urgently. As a new subclass of endogenous noncoding RNAs, circRNAs are present in eukaryotic cells and have the capacity of sponging miRNAs, combing with RNAbinding proteins and working as transcription factors[4]
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