Abstract
Background Chemoresistance is a major obstacle to the treatment of osteosarcoma patients. Circular RNA (circRNA) circPVT1 has been reported to be related to the doxorubicin (DXR) resistance in osteosarcoma. This study is designed to explore the role and mechanism of circPVT1 in the DXR resistance of osteosarcoma. Methods circPVT1, microRNA-137 (miR-137), and TP53-regulated inhibitor of apoptosis 1 (TRIAP1) levels were detected by real-time quantitative polymerase chain reaction (RT-qPCR). The protein levels of ATP-binding cassette, subfamily C, member 1 (ABCC1), multidrug resistance-associated protein 1 (MRP-1), cleaved- (c-) caspase-3, B-cell lymphoma-2 (Bcl-2), and TRIAP1 were examined by a western blot assay. Cell viability, proliferation, and apoptosis were detected by cell counting kit-8 (CCK-8), colony formation, and flow cytometry assays, severally. The binding relationship between miR-137 and circPVT1 or TRIAP1 was predicted by starbase 3.0 and then verified by dual-luciferase reporter and RNA Immunoprecipitation (RIP) assays. The biological role of circPVT1 in osteosarcoma tumor growth and drug resistance was examined by the xenograft tumor model in vivo. Results. circPVT1 and TRIAP1 were highly expressed, and miR-137 was decreased in DXR-resistant osteosarcoma tissues and cells. Moreover, circPVT1 knockdown could boost DXR sensitivity by inhibiting DXR-caused proliferation and DXR-induced apoptosis in DXR-resistant osteosarcoma cells in vitro. The mechanical analysis discovered that circPVT1 acted as a sponge of miR-137 to regulate TRIAP1 expression. circPVT1 silencing increased the drug sensitivity of osteosarcoma in vivo. Conclusion. circPVT1 boosted DXR resistance of osteosarcoma cells partly by regulating the miR-137/TRIAP1 axis, hinting a promising therapeutic target for the osteosarcoma treatment.
Highlights
Osteosarcoma, which occurs mainly in children and adolescents, is the most common malignant bone tumor [1, 2]
Western blot results suggested that the inhibition of B-cell lymphoma-2 (Bcl-2), ABCB1, and multidrug resistance-associated protein 1 (MRP-1) and the promotion of c-caspase-3 due to the circPVT1 knockdown were reversed by miR-137 inhibitor in KHOS/DXR and U2OS/DXR cells (Figure 4(e)). All of these results suggested that the downregulation of miR-137 could partly abolish the circPVT1silencing-induced DXR sensitivity in DXR-resistant osteosarcoma cells
We further proved that both mRNA level and protein level of TP53regulated inhibitor of apoptosis 1 (TRIAP1) were distinctly upregulated in the DXR-resistant osteosarcoma cells (KHOS/DXR and U2OS/DXR) in comparison with other cells (Figures 5(e) and 5(f))
Summary
Osteosarcoma, which occurs mainly in children and adolescents, is the most common malignant bone tumor [1, 2]. CircRNAs are widely expressed in mammalian cells and have been reported to regulate gene expression at different levels [7]. CircRNAs have been reported to be closely related to chemoresistance in a variety of cancers, including osteosarcoma. CircPVT1 was presented to be increased in osteosarcoma and facilitated the doxorubicin (DXR) resistance of osteosarcoma cells [13, 14]. Circular RNA (circRNA) circPVT1 has been reported to be related to the doxorubicin (DXR) resistance in osteosarcoma. CircPVT1 and TRIAP1 were highly expressed, and miR-137 was decreased in DXR-resistant osteosarcoma tissues and cells. CircPVT1 boosted DXR resistance of osteosarcoma cells partly by regulating the miR-137/TRIAP1 axis, hinting a promising therapeutic target for the osteosarcoma treatment Conclusion. circPVT1 boosted DXR resistance of osteosarcoma cells partly by regulating the miR-137/TRIAP1 axis, hinting a promising therapeutic target for the osteosarcoma treatment
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