Lnc NEAT1/miR-29b-3p/Sp1 form a positive feedback loop and modulate bortezomib resistance in human multiple myeloma cells

Eur J Pharmacol. 2021 Jan 15;891:173752. doi: 10.1016/j.ejphar.2020.173752. Epub 2020 Nov 28.

Abstract

The overall survival of multiple myeloma (MM) patients significantly improved with the use of proteasome inhibitor such as bortezomib. However, resistance to sorafenib limits its use. Bortezomib-resistant MM cells were generated and their bortezomib-resistant properties were confirmed by cell viability and apoptosis assays. To explore functions and underlying mechanisms of long non-coding RNA nuclear paraspeckle assembly transcript 1 (NEAT1) on bortezomib resistance in MM, MTT assays, flow cytometry analyses, dual luciferase report gene assays, RNA pulldown assays and chromatin immunoprecipitation assays were carried out. NEAT1 and specific protein 1 (Sp1) was upregulated while miR-29b-3p was down regulated in bortezomib-resistant MM cells. NEAT1 promoted Sp1 expression by sponging miR-29b-3p and then enhanced the tolerance of MM cells to bortezomib. Sp1 targeted to NEAT1 promoter region promoting NEAT1 transcription and formed a positive feedback loop. NEAT1 and Sp1 levels were higher and miR-29b-3p was levels were lower in bortezomib-resistant MM patients. NEAT1/miR-29b-3p/Sp1 feedback loop enhanced the tolerance of MM cells to bortezomib. These results indicate potentially valuable targets for overcoming bortezomib resistance for MM.

Keywords: Bortezomib; Multiple myeloma; NEAT1; Resistance; Sp1; miR-29b-3p.

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Bortezomib / pharmacology*
  • Case-Control Studies
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm* / genetics
  • Feedback, Physiological
  • Gene Expression Regulation, Neoplastic
  • Humans
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Multiple Myeloma / drug therapy*
  • Multiple Myeloma / genetics
  • Multiple Myeloma / metabolism
  • Multiple Myeloma / pathology
  • Proteasome Inhibitors / pharmacology*
  • RNA, Long Noncoding / genetics
  • RNA, Long Noncoding / metabolism*
  • Sp1 Transcription Factor / genetics
  • Sp1 Transcription Factor / metabolism*

Substances

  • Antineoplastic Agents
  • MIRN29a microRNA, human
  • MicroRNAs
  • NEAT1 long non-coding RNA, human
  • Proteasome Inhibitors
  • RNA, Long Noncoding
  • Sp1 Transcription Factor
  • Sp1 protein, human
  • Bortezomib