CircRNA ITCH increases bortezomib sensitivity through regulating the miR-615-3p/PRKCD axis in multiple myeloma

Life Sci. 2020 Dec 1:262:118506. doi: 10.1016/j.lfs.2020.118506. Epub 2020 Oct 5.


Aims: Bortezomib (BTZ) is described as the first-line agent for multiple myeloma (MM) chemotherapy, but the emergence of BTZ resistance usually results in the failure of chemotherapy in MM. Circular RNA (circRNA) itchy E3 ubiquitin protein ligase (circITCH) is a novel identified circRNA that plays a vital role in the development of human cancers. However, the role of circITCH in the development of BTZ resistance in MM remains elusive.

Materials and methods: The expression of circITCH, miR-615-3p, and protein kinase C, delta (PRKCD) was detected with quantitative reverse transcription PCR and western blot. The effects of circITCH on the sensitivity of MM cells to BTZ were assessed using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay, flow cytometry, and xenograft tumor assay. The interaction of circITCH, microRNA-615-3p, and PRKCD was explored using luciferase reporter assay and RNA immunoprecipitation assay.

Key findings: circITCH was downregulated in MM bone marrow specimens and cell lines, as well as BTZ-resistant MM cells. Reduced expression of circITCH was indicative of poor prognosis in MM patients. Upregulation of circITCH enhanced the sensitivity of BTZ-resistant MM cells to BTZ in vitro and in vivo. Furthermore, circITCH was identified as a sponge for miR-615-3p, and PRKCD is confirmed as a direct target of miR-615-3p. Besides, circITCH overexpression enhanced the sensitivity of MM cells to BTZ through miR-615-3p/PRKCD axis.

Significance: circITCH overexpression enhanced the sensitivity of MM cells to BTZ through miR-615-3p/PRKCD axis, providing a novel potential target for combating BTZ resistance in patients with MM.

Keywords: Bortezomib; Delta; Multiple myeloma; Protein kinase C; circITCH; miR-615-3p.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Bortezomib / pharmacology*
  • Cell Line, Tumor
  • Down-Regulation
  • Drug Resistance, Neoplasm / genetics
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • MicroRNAs / genetics
  • Multiple Myeloma / drug therapy*
  • Multiple Myeloma / genetics
  • Protein Kinase C-delta / genetics
  • Repressor Proteins / genetics*
  • Ubiquitin-Protein Ligases / genetics*
  • Up-Regulation
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • MIRN615 microRNA, human
  • MicroRNAs
  • Repressor Proteins
  • Bortezomib
  • ITCH protein, human
  • Ubiquitin-Protein Ligases
  • PRKCD protein, human
  • Protein Kinase C-delta