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Tanshinone I restrains osteosarcoma progression by regulating circ_0000376/miR-432-5p/BCL2 axis

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Abstract

Circular RNAs (circRNAs) have been identified as important regulators in cancer progression. Nevertheless, little is known about the biological function of circ_0000376 in the progression of osteosarcoma (OS). Cell viability, colony formation ability, apoptosis, and motility were analyzed by Cell Counting Kit-8 assay, colony formation assay, flow cytometry, and transwell assays. Cellular glycolytic metabolism was analyzed using commercial kits. RT-qPCR and Western blot assay were performed to analyze RNA and protein expression in OS tissues and cells. Starbase software was used to establish circRNA–microRNA (miRNA)–messenger RNA linkage, and intermolecular interaction was verified by dual-luciferase reporter assay. Xenograft tumor assay was conducted to analyze the effects of Tanshinone I (Tan I) and circ_0000376 on xenograft tumor growth in vivo. Tan I treatment suppressed the viability, migration, invasion, and glycolysis and triggered the apoptosis of OS cells. Tan I treatment markedly down-regulated circ_0000376 expression in OS cells. The addition of circ_0000376 plasmid largely rescued the malignant behaviors of OS cells upon Tan I exposure. Circ_0000376 interacted with miR-432-5p in OS cells. Circ_0000376 overexpression-mediated protective effects in Tan I-induced OS cells were partly attenuated by the accumulation of miR-432-5p. miR-432-5p bound to the 3ʹ untranslated region (3ʹUTR) of B-cell leukemia/lymphoma 2 (BCL2) in OS cells. miR-432-5p interference-induced effects in Tan I-treated OS cells were partly overturned by the silence of BCL2. Circ_0000376 can act as miR-432-5p sponge to up-regulate BCL2 expression in OS cells. Circ_0000376 silencing contributed to the anti-tumor effect of Tan I on the growth of xenograft tumors in vivo. Tan I exerted an anti-tumor role in OS progression by targeting circ_0000376/miR-432-5p/BCL2 axis.

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  1. Baoguo Ye and Kong Qiao have contributed equally to this paper.

Authors and Affiliations

  1. Department of Anesthesiology, China-Japan Union Hospital Jilin University, No. 126 Xiantai Street, Changchun City, 234000, Jilin Province, China

    Baoguo Ye

  2. Department of Orthopedics, The Hospital of Bayannaoer, BayanNur City, Inner Mongolia, China

    Kong Qiao

  3. Department of Orthopedics, China-Japan Union Hospital Jilin University, Changchun City, Jilin Province, China

    Qiheng Zhao, Zhigang Jiang & Fei Wang

  4. Key Laboratory of Jilin Province for Zoonosis Prevention and Control Military Veterinary Institute, Academy of Military Medical Sciences, Changchun City, Jilin Province, China

    Ningning Hu

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Contributions

BY and KQ conceived and designed the experiments, participated in its design and coordination, and helped to draft and revise the manuscript. QZZJ, NH, and FW collected the samples and clinical data and performed the experiments and the statistical analysis. All authors read and approved the final manuscript.

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Correspondence to Fei Wang.

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All experimental procedures were in strict conformity to the guidelines on the use of laboratory animals and approved by China-Japan Union Hospital Jilin University.

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Supplementary Information

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11010_2021_4257_MOESM1_ESM.tif

Supplementary Fig. 1. Tan I treatment suppresses the viability and colony formation ability of OS cells. (A-F) We treated U2OS, MG63, and 143B cells with increased doses (0.08 μmol/L, 0.4 μmol/L or 2 μmol/L) of Tan I for 24 h. (A-C) Cell viability was measured by CCK8 assay. (D-F) Colony formation assay was used to assess the colony formation ability of Tan I-treated OS cells. *: P < 0.05. Supplementary file1 (TIF 2865 kb)

11010_2021_4257_MOESM2_ESM.tif

Supplementary Fig. 2. Tan I treatment reduces the expression of circ_0000376 in HOS, 143B, and ZOS cell lines. (A-C) RT-qPCR was conducted to analyze the expression of circ_0000376 in HOS, 143B, and ZOS cells treated with 2 μmol/L Tan I for 24 h. *: P < 0.05. Supplementary file2 (TIF 200 kb)

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Ye, B., Qiao, K., Zhao, Q. et al. Tanshinone I restrains osteosarcoma progression by regulating circ_0000376/miR-432-5p/BCL2 axis. Mol Cell Biochem 477, 1–13 (2022). https://doi.org/10.1007/s11010-021-04257-4

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