Circ_0017274 acts on miR-637/CDX2 axis to facilitate cisplatin resistance in gastric cancer

Clin Exp Pharmacol Physiol. 2022 Oct;49(10):1105-1115. doi: 10.1111/1440-1681.13692. Epub 2022 Jul 21.

Abstract

Currently, a substantial amount of circular RNAs (circRNAs) are closely associated with cancer development and the occurrence of drug resistance, however, circ_0017274 in cisplatin (CDDP) resistance in gastric cancer (GC) has not been addressed. Real-time quantitative polymerase chain reaction (RT-qPCR) and western blot were utilized for circ_0017274, microRNA-637 (miR-637) and caudal-related homeobox transcription factor 2 (CDX2) contents analysis. Analysis of IC50, proliferation, cell cycle, apoptosis, migration and invasion of GC cells using Cell Counting Kit-8 (CCK8), 5-ethynyl-2'-deoxyuridine (EdU), flow cytometry or transwell assays. Interaction between miR-637 and circ_0017274 or CDX2 was validated under the application of luciferase reporter system, RNA immunoprecipitation (RIP) analysis, and pull-down assay. The effect of circ_0017274 on CDDP sensitivity in vivo was tapped by xenograft models. Circ_0017274 and CDX2 had higher content in CDDP-resistant GC tissues and cells, while miR-637 had lower content. CDDP resistance and development of GC cells were arrested when circ_0017274 level was reduced in vitro. MiR-637 acted as a target of circ_0017274, and miR-637 downregulation abated the phenomenon of elevated sensitivity of sh-circ_0017274 to CDDP. MiR-637 was also demonstrated to interact with CDX2 and to co-regulate CDDP sensitivity in GC cells. The xenograft models also established that circ_0017274 downregulation strengthened CDDP sensitivity and thus curtailed tumour growth in vivo. Circ_0017274 downregulation boosted CDDP sensitivity by acting on miR-637/CDX2 in CDDP-resistant GC cells.

Keywords: CDDP; CDX2; circ_0017274; gastric cancer; miR-637.

MeSH terms

  • CDX2 Transcription Factor* / genetics
  • CDX2 Transcription Factor* / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Cisplatin / pharmacology
  • Drug Resistance, Neoplasm
  • Humans
  • MicroRNAs* / genetics
  • MicroRNAs* / metabolism
  • RNA, Circular* / genetics
  • Stomach Neoplasms* / drug therapy
  • Stomach Neoplasms* / genetics
  • Stomach Neoplasms* / metabolism

Substances

  • CDX2 Transcription Factor
  • CDX2 protein, human
  • MIRN637 microRNA, human
  • MicroRNAs
  • RNA, Circular
  • Cisplatin