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

Abstract

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.

Non-coding RNAs in drug and radiation resistance of bone and soft-tissue sarcoma: a systematic review

“…Of these, 43 investigated the molecular regulatory mechanisms of lncRNAs in chemotherapeutic drug resistance in OS, 101 focused on miRNAs, 21 on circRNAs, and one study reported on both lncRNA MEG3 and hsa_circ_0001258 ( Zhu et al, 2019 ). Moreover, 19 overlapping ncRNAs were reported in more than one study, including four lncRNAs (lncRNA SNHG15 [ Sun et al, 2022 ; Zhang et al, 2020a ], lncRNA OIP5-AS1 [ Song et al, 2019 ; Liu and Wang, 2020 ; Sun et al, 2020 ; Kun-Peng et al, 2019 ], lncRNA TUG1 [ Zhou et al, 2020 ; Hu et al, 2019 ], and lncRNA ANRIL [ Li and Zhu, 2019b ; Lee et al, 2021 ]), 13 miRNAs (miR-29b [ Luo et al, 2019 ; Li et al, 2020 ], miR-21 [ Vanas et al, 2016 ; Ziyan and Yang, 2016 ], miR-22 [ Wang et al, 2019c ; Li et al, 2014 ; Meng et al, 2020a ; Meng et al, 2020b ; Zhou et al, 2018b ], miR-199a-3p [ Lei et al, 2018 ; Gao et al, 2015 ], miR-34a-5p [ Pu et al, 2016 ; Pu et al, 2017b ; Pu et al, 2017a ], miR-34a [ Li et al, 2017 ; Novello et al, 2014 ; Chen et al, 2016a ], miR-140-5p [ Wei et al, 2016 ; Meng et al, 2017 ], miR-203 [ Chen et al, 2016a ; Huang et al, 2021 ], miR-19a-3p [ Zhang et al, 2019 ; Wang et al, 2022a ], miR-140 [ Song et al, 2009 ; Zhi et al, 2022 ], miR-29 [ Osaki et al, 2016 ; Xu et al, 2018b ], miR-221 [ Yu et al, 2019 ; Zhao et al, 2013 ], and miR-100 [ Xiao et al, 2017 ; Liu et al, 2016 ]), and two circRNAs (circPTV1 [ Li et al, 2021c ; Kun-Peng et al, 2018a ; Wang et al, 2022c ] and circRNA_0004674 [ Ma et al, 2021 ; Bai et al, 2021 ]) (…”

The Role of Circular RNAs in the Drug Resistance of Cancers

“…Similarly, hsa_circ_0000073 promotes malignant behaviors, including proliferation, invasion, and migration, and facilitates MTX resistance of osteosarcoma cells by sponging miR-145-5p and miR-151-3p to upregulate NRAS (105). DOX resistance of osteosarcoma is facilitated by hsa_circ_0004674 through the Wnt/b-catenin pathway via modulation of the miR-342-3p/FBN1 axis (106). Moreover, some circRNAs potentiate DOX resistance and facilitate the progression of osteosarcomas, such as circ_0001721, circSAMD4A, circ_0002060, and circ_0003496 (20,(107)(108)(109).…”

“…DOX resistance of osteosarcoma is facilitated by hsa_circ_0004674 through the Wnt/β-catenin pathway via modulation of the miR-342-3p/FBN1 axis ( 106 ). Moreover, some circRNAs potentiate DOX resistance and facilitate the progression of osteosarcomas, such as circ_0001721, circSAMD4A, circ_0002060, and circ_0003496 ( 20 , 107 – 109 ).…”

Dissecting the Role of Circular RNAs in Sarcomas with Emphasis on Osteosarcomas

“…Moreover, new evidence implies that circRNAs may affect acquired chemoresistance [ 87 ]. The above-mentioned mechanisms have been shown to be critical in sarcomagenesis [ 88 , 89 , 90 , 91 , 92 , 93 , 94 ], and a large number of circRNAs have been demonstrated to affect chemoresistance in OS, such as hsa_circ_0004674, hsa_circ_0081001 and circPVT1, among others [ 88 , 95 , 96 , 97 , 98 ].…”

“…According to previous research findings of this group, chemoresistance in OS may be regulated by hsa_circ_0004674-miR-490-3p-ABCC2 and hsa_circ_0004674/miR-1254-EGFR pathways [ 96 , 240 , 241 ]. In addition, Bai et al proposed a new mechanism of hsa_circ_0004674 promoting chemoresistance to DXR by regulating the miR-342-3p/FBN1 axis through the Wnt/β-catenin pathway [ 88 ].…”