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Circ_0001667 Promotes Adriamycin Resistance and Malignant Progression via Targeting the miR-193a-5p/Rap2A Molecular Axis in Breast Cancer

Published:September 30, 2022DOI:https://doi.org/10.1016/j.clbc.2022.09.008

      Highlights

      • Adriamycin resistance and cell development are retarded after downregulation of circ_0001667 in resistant breast cancer (BC) cells.
      • Circ_0001667 knockdown reduces tumor growth in adriamycin-resistant xenograft model.
      • Circ_0001667 serves as a sponge of miR-193a-5p to regulate the expression of Rap2A.

      Abstract

      Background

      The therapeutic effect of adriamycin (ADM) has been limited by chemoresistance in breast cancer (BC). Circular RNAs are involved in resistance regulation by mediating the miRNA/mRNA axis. Circ_0001667 enhanced ADM resistance via the miR-4458/NCOA3 axis in BC. This study was to investigate the other miRNA/mRNA network for circ_0001667.

      Methods

      The level detection of circ_0001667, microRNA-193a-5p (miR-193a-5p) or Ras-Related Protein 2a (Rap2A) was conducted by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Half inhibitory concentration (IC50) of ADM was detected through cell counting kit-8 (CCK-8) assay. The proliferation analysis was performed by colony formation assay and EdU assay. Flow cytometry was used for assessing apoptosis. Transwell assay was applied for examining cell migration and invasion. The protein detection was carried out by western blot. In vivo assay was performed using xenograft tumor model. Dual-luciferase reporter and RNA immunoprecipitation (RIP) assays were implemented to validate the target interaction.

      Results

      Circ_0001667 was highly expressed in ADM-resistant BC tissues and cells. Downregulation of circ_0001667 reduced ADM resistance and inhibited proliferation, migration, invasion in ADM-resistant BC cells. Tumor growth was repressed by circ_0001667 knockdown in ADM-resistant xenograft model. Circ_0001667 has induced the sponge effect on miR-193a-5p. The circ_0001667 function was partly achieved by targeting miR-193a-5p. Rap2A expression was positively regulated by circ_0001667 through sponging miR-193a-5p. The miR-193a-5p upregulation restrained chemoresistance and BC progression by the downregulation of Rap2A.

      Conclusion

      All results unraveled that circ_0001667 contributed to ADM resistance and tumor development in BC via the miR-193a-5p-mediated Rap2A expression change, providing a novel regulatory mechanism for circ_0001667.

      Keywords

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