Hsa_circ_0004674 promotes osteosarcoma doxorubicin resistance by regulating the miR-342-3p/FBN1 axis

J Orthop Surg Res. 2021 Aug 18;16(1):510. doi: 10.1186/s13018-021-02631-y.


Background: The occurrence of chemoresistance is a common problem in tumor treatment. Circular RNA (circRNA) has been confirmed to be related to tumor chemoresistance. However, the role and the underlying molecular mechanism of hsa_circ_0004674 in the chemoresistance of osteosarcoma (OS) are still unclear.

Methods: The expression of hsa_circ_0004674, miR-342-3p, and fibrillin-1 (FBN1) was determined by qRT-PCR. Cell counting kit 8 assay was used to evaluate the doxorubicin (DXR) resistance of cells. The proliferation and apoptosis of cells were measured using colony formation assay and flow cytometry. Western blot analysis was utilized to examine the protein levels of resistance markers, Wnt/β-catenin pathway markers and FBN1. The interaction between miR-342-3p and hsa_circ_0004674 or FBN1 was confirmed by dual-luciferase reporter assay and RNA pull-down assay. Moreover, animal experiments were performed to assess the effect of hsa_circ_0004674 silencing on the DXR sensitive of OS in vivo.

Results: The upregulated hsa_circ_0004674 was found in DXR-resistant OS tissues and cells. Knockdown of hsa_circ_0004674 could inhibit the DXR resistance of OS cells in vitro and promote the DXR sensitive of OS tumors in vivo. In addition, we discovered that hsa_circ_0004674 could sponge miR-342-3p, and miR-342-3p could target FBN1. MiR-342-3p inhibitor could reverse the inhibition effect of hsa_circ_0004674 knockdown on the DXR resistance of OS cells. Similarly, the suppressive effect of miR-342-3p on the DXR resistance of OS cells also could be reversed by FBN1 overexpression. Furthermore, we revealed that hsa_circ_0004674 silencing inhibited the activity of Wnt/β-catenin pathway by the miR-342-3p/FBN1 axis.

Conclusion: Hsa_circ_0004674 facilitated the DXR resistance of OS through Wnt/β-catenin pathway via regulating the miR-342-3p/FBN1 axis, suggesting that hsa_circ_0004674 was a promising target for the chemoresistance of OS.

Keywords: FBN1; Osteosarcoma; chemoresistance; hsa_circ_0004674; miR-342-3p.

MeSH terms

  • Animals
  • Bone Neoplasms*
  • Cell Line, Tumor
  • Cell Proliferation
  • Doxorubicin / pharmacology
  • Fibrillin-1
  • MicroRNAs* / genetics
  • Osteosarcoma* / drug therapy
  • Osteosarcoma* / genetics
  • beta Catenin


  • Fibrillin-1
  • MicroRNAs
  • beta Catenin
  • Doxorubicin