Exosomal transfer of circular RNA FBXW7 ameliorates the chemoresistance to oxaliplatin in colorectal cancer by sponging miR-18b-5p

Neoplasma. 2021 Jan;68(1):108-118. doi: 10.4149/neo_2020_200417N414. Epub 2020 Nov 5.

Abstract

Circular RNA F-box and WD repeat domain containing 7 (circ-FBXW7) has been revealed to be involved in the tumorigenesis of colorectal cancer (CRC). Exosomes are critical mediators of intercellular communication. However, the role of exosomal circ-FBXW7 in the CRC oxaliplatin resistance remains unknown. Cell viability, apoptosis, motility, and drug efflux were measured by the cell counting kit-8 assay, flow cytometry, transwell assay, and atomic absorption spectrophotometry, respectively. The expression of circ-FBXW7 and microRNA (miR)-18b-5p was detected using the quantitative real-time polymerase chain reaction. Western blot was used to determine multidrug resistance protein 1 (MRP1), myeloid cell leukemia-1 (MCL-1), CD9, CD63, Caspase3, E-cadherin, and N-cadherin. Exosomes were isolated and captured using the ultracentrifugation method and transmission electron microscopy. The interaction between circ-FBXW7 and miR-18b-5p was confirmed by dual-luciferase reporter assay and RNA immunoprecipitation assay. In vivo experiments were conducted using the murine xenograft model. Our results showed that circ-FBXW7 was decreased in oxaliplatin-resistant CRC patients and cells. circ-FBXW7 was secreted by circ-FBXW7-transfected FHC cells and could be transferred to resistant CRC cells through the exosome secretion. Subsequently, in vitro and in vivo studies demonstrated exosomal circ-FBXW7 led resistant cells sensitive to oxaliplatin, increased the oxaliplatin-induced apoptosis, inhibited oxaliplatin-induced epithelial-mesenchymal transition, and suppressed oxaliplatin efflux. miR-18b-5p was increased in oxaliplatin-resistant CRC patients and cells and was confirmed to be a target of circ-FBXW7. Immediately, the rescue assay showed exosome-mediated transfer of circ-FBXW7 enhanced oxaliplatin sensitivity by binding to miR-18b-5p in vitro and in vivo. To conclude, the circ-FBXW7 delivery by exosomes could ameliorate chemoresistance to oxaliplatin in CRC by directly binding to miR-128-3p, suggesting a promising therapeutic strategy for oxaliplatin-resistant CRC patients.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Colorectal Neoplasms* / drug therapy
  • Colorectal Neoplasms* / genetics
  • Drug Resistance, Neoplasm
  • Exome
  • F-Box-WD Repeat-Containing Protein 7* / genetics
  • Humans
  • Mice
  • MicroRNAs* / genetics
  • MicroRNAs* / metabolism
  • Oxaliplatin* / pharmacology
  • RNA, Circular / genetics
  • RNA, Circular / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • F-Box-WD Repeat-Containing Protein 7
  • FBXW7 protein, human
  • MIRN18 microRNA, human
  • MicroRNAs
  • RNA, Circular
  • Oxaliplatin