Abstract
Background: Osteosarcoma (OS) is a common, aggressive primary sarcoma of bone. Drug resistance is a huge obstacle to chemotherapy for cancer. This study aimed to investigate the role and mechanism of circ_0002060 in OS resistance to doxorubicin (DOX). Methods: The levels of circ_0002060, miR-198, and ATP-binding cassette subfamily B member 1 (ABCB1) in OS tissues and DOX-resistant OS cells were measured by quantitative real-time polymerase chain reaction or western blot assay. Kaplan-Meier analysis was performed to determine the relationship between circ_0002060 expression in OS tissues and overall survival of OS patients. The half-inhibitory concentration (IC50) of DOX was calculated using the Cell Counting Kit-8 (CCK-8) assay. Proliferation and apoptosis of DOX-resistant OS cells were assessed by colony formation assay and flow cytometry. The levels of apoptosis-related proteins in DOX-resistant OS cells were measured by western blot assay. Xenograft assay was utilized to analyze the effect of circ_0002060 on DOX resistance in vivo. The interactions among circ_0002060, miR-198, and ABCB1 in DOX-resistant OS cells were confirmed by dual-luciferase reporter assay, RNA immunoprecipitation assay, or RNA pull-down assay. Results: circ_0002060 and ABCB1 were upregulated, while miR-198 was downregulated in OS tissues and DOX-resistant OS cells. circ_0002060 silencing reduced DOX resistance in vitro and in vivo. Moreover, circ_0002060 enhanced DOX resistance by sponging miR-198. Besides, miR-198 decreased DOX resistance by binding to ABCB1. In addition, circ_0002060 sponged miR-198 to upregulate ABCB1 expression. Conclusions: circ_0002060 promoted DOX resistance and OS progression by regulating the miR-198/ABCB1 axis, suggesting that circ_0002060 might be a promising biomarker for OS therapy.
Highlights
Osteosarcoma (OS) is a common aggressive primary sarcoma of bone
The interaction among circ_0002060, miR-198 and ATP binding cassette subfamily B member 1 (ABCB1) were confirmed by dual-luciferase reporter assay, RNA immunoprecipitation assay or RNA pulldown assay
Circ_0002060 and ABCB1 were up-regulated, while miR-198 was down-regulated in OS tissues and DOX-resistant OS cells
Summary
Osteosarcoma (OS) is a common aggressive primary sarcoma of bone. Drug resistance is a huge obstacle to chemotherapy for cancer. This study aimed to investigate the role and mechanism of circ_0002060 in OS resistance to doxorubicin (DOX). Methods The levels of circ_0002060, miR-198 and ATP binding cassette subfamily B member 1 (ABCB1) were measured by quantitative real-time polymerase chain reaction or western blot assay. Xenograft assay was utilized to analyze the effect of circ_0002060 on DOX resistance in vivo. Results Circ_0002060 and ABCB1 were up-regulated, while miR-198 was down-regulated in OS tissues and DOX-resistant OS cells. Circ_0002060 enhanced DOX resistance via sponging miR-198. MiR-198 decreased DOX resistance by binding to ABCB1. Circ_0002060 sponged miR-198 to up-regulate ABCB1 expression. Conclusion Circ_0002060 enhanced doxorubicin resistance of OS by regulating miR198/ABCB1 axis, which provides potential therapeutic targets for OS therapy. Circ_0002060 expression was analyzed in OS, and we first found that circ_0002060 was markedly up-regulated, hinting its potential role in OS development
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