circ-LDLRAD3 Knockdown Reduces Cisplatin Chemoresistance and Inhibits the Development of Gastric Cancer with Cisplatin Resistance through miR-588 Enrichment-Mediated SOX5 Inhibition

Gut Liver. 2023 May 15;17(3):389-403. doi: 10.5009/gnl210195. Epub 2022 Aug 17.


Background/aims: Chemoresistance is a common event after cancer chemotherapy, which is associated with the deregulation of circular RNAs (circRNAs). The objective of this study was to clarify the role of circ-LDLRAD3 in cisplatin (DDP)-resistant gastric cancer (GC).

Methods: The expression of circ-LDLRAD3, miR-588, and SRY-box transcription factor 5 (SOX5) mRNA was detected by quantitative real-time polymerase chain reaction. Cell viability and the half maximal inhibitory concentration (IC50) value were measured by CCK8 assay. Cell proliferation was assessed by colony formation and EdU assays. Cell apoptosis and cell invasion were assessed by flow cytometry assay and transwell assay, respectively. The expression of SOX5 protein was detected by Western blotting. A xenograft model was established to verify the role of circ-LDLRAD3 in vivo. Exosomes were isolated by differential centrifugation and identified by transmission electron microscopy and the expression of exosome-related proteins.

Results: circ-LDLRAD3 was overexpressed in DDP-resistant GC tissues and cells. circ-LDLRAD3 knockdown decreased the IC50 of DDP-resistant cells and suppressed cell proliferation, survival and invasion. miR-588 was a target of circ-LDLRAD3, and miR-588 inhibition attenuated the inhibition of DDP resistance, proliferation, survival and invasion in DDP-resistant GC cells caused by circ-LDLRAD3 knockdown. SOX5 was a target of miR-588, and the inhibition of the DDP resistance, proliferation, survival and invasion of DDP-resistant GC cells by miR-588 restoration was largely rescued SOX5 overexpression. circ-LDLRAD3 knockdown inhibited DDP resistance and tumor growth in vivo. circ-LDLRAD3 was overexpressed in exosomes isolated from DDP-resistant GC cells.

Conclusions: circ-LDLRAD3 knockdown reduced DDP resistance and blocked the malignant development of DDP-resistant GC by modulating the miR-588/SOX5 pathway.

Keywords: Cisplatin; SOX5; Stomach neoplasms; circ-LDLRAD3; miR-588.

MeSH terms

  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Cisplatin / pharmacology
  • Drug Resistance, Neoplasm / genetics
  • Humans
  • MicroRNAs* / genetics
  • SOXD Transcription Factors / genetics
  • Stomach Neoplasms* / drug therapy
  • Stomach Neoplasms* / genetics


  • Cisplatin
  • MicroRNAs
  • SOX5 protein, human
  • SOXD Transcription Factors
  • MIRN588 microRNA, human

Grants and funding

ACKNOWLEDGEMENTS This work was supported by Medical science and technology research plan of Henan Province in 2020 (Key projects jointly built by provinces and ministries) (grant number: SBGJ202002128).