miRNA-223-3p modulates ibrutinib resistance through regulation of the CHUK/Nf-κb signaling pathway in mantle cell lymphoma

Exp Hematol. 2021 Nov;103:52-59.e2. doi: 10.1016/j.exphem.2021.08.010. Epub 2021 Aug 30.


Since the use of Bruton's tyrosine kinase (BTK) inhibitor ibrutinib in relapsed/refractory (R/R) mantle cell lymphoma (MCL), the problem of drug resistance has become increasingly prominent. Though it has been proven that the nonclassic nuclear factor κB pathway (nonclassic NF-κB pathway) correlates with ibrutinib resistance in MCL, the upstream regulator is unknown. In the present study, conserved helix-loop-helix ubiquitous kinase (CHUK) overexpression accelerated proliferation and suppressed apoptosis of MCL cells after ibrutinib treatment in vitro. The results of luciferase reporter assay, real-time quantitative polymerase chain reaction (RT-qPCR), and Western blot revealed that CHUK was targeted and negatively regulated by miRNA-223-3p. miRNA-223-3p knockdown promoted proliferation and inhibited apoptosis of MCL cells after ibrutinib treatment in vitro and vivo, whereas CHUK knockdown reversed downregulated miRNA-223-3p-promoted cell proliferation after ibrutinib treatment in vitro. In conclusion, miRNA-223-3p modulates ibrutinib resistance through regulation of the CHUK/NF-κB signaling pathway in MCL, which is crucial in providing a marker to predict disease response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine / analogs & derivatives*
  • Adenine / pharmacology
  • Adenine / therapeutic use
  • Animals
  • Drug Resistance, Neoplasm
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • I-kappa B Kinase / metabolism
  • Lymphoma, Mantle-Cell / drug therapy*
  • Lymphoma, Mantle-Cell / genetics
  • Lymphoma, Mantle-Cell / metabolism
  • Mice, Inbred BALB C
  • Mice, Nude
  • MicroRNAs / genetics*
  • NF-kappa B / metabolism
  • Piperidines / pharmacology
  • Piperidines / therapeutic use*
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use*
  • Signal Transduction / drug effects*


  • MIRN223 microRNA, human
  • MIRN223 microRNA, mouse
  • MicroRNAs
  • NF-kappa B
  • Piperidines
  • Protein Kinase Inhibitors
  • ibrutinib
  • I-kappa B Kinase
  • Adenine