DNA methylation-mediated silencing of microRNA-204 enhances T cell acute lymphoblastic leukemia by up-regulating MMP-2 and MMP-9 via NF-κB

J Cell Mol Med. 2021 Mar;25(5):2365-2376. doi: 10.1111/jcmm.15896. Epub 2021 Feb 10.

Abstract

T cell acute lymphoblastic leukaemia (T-ALL) is a highly aggressive haematological cancer of the bone marrow. The abnormal expression of microRNAs (miRNAs) is reportedly involved in T-ALL development and progression. Thus, we aimed to decipher the involvement of miR-204 silencing mediated by DNA methylation in the occurrence of T cell acute lymphoblastic leukaemia (T-ALL). miR-204 expression was determined in bone marrow and peripheral blood samples from T-ALL patients by real-time quantitative PCR (RT-qPCR) with its effect on cell proliferation evaluated by functional assays. In addition, bisulphite sequencing PCR was employed to detect the DNA methylation level of the miR-204 promoter region, and the binding site between miR-204 and IRAK1 was detected by luciferase assay. We found that miR-204 was down-regulated in T cells of T-ALL patients, which was caused by the increased DNA methylation in the promoter region of miR-204. Moreover, overexpression of miR-204 inhibited T-ALL cell proliferation while enhancing their apoptosis through interleukin receptor-associated kinase 1 (IRAK1), which enhanced the expression of matrix metalloproteinase-2 (MMP-2) and MMP-9 through activation of p-p65. Thus, miR-204 modulated MMP-2 and MMP-9 through IRAK1/NF-κB signalling pathway, which was confirmed by in vivo assay. Taken together, DNA methylation-mediated miR-204 silencing increased the transcription of IRAK1, thus activating the NF-κB signalling pathway and up-regulating the downstream targets MMP-2/MMP-9.

Keywords: DNA methylation; IRAK1; NF-κB; T cell acute lymphoblastic leukaemia; miR-204.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Animals
  • Apoptosis / genetics
  • Cell Proliferation
  • DNA Methylation*
  • Disease Models, Animal
  • Female
  • Gene Expression Regulation, Leukemic
  • Gene Silencing*
  • Humans
  • Interleukin-1 Receptor-Associated Kinases / genetics
  • Matrix Metalloproteinase 2 / genetics*
  • Matrix Metalloproteinase 2 / metabolism
  • Matrix Metalloproteinase 9 / genetics*
  • Matrix Metalloproteinase 9 / metabolism
  • Mice
  • MicroRNAs / genetics*
  • NF-kappa B / metabolism*
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics*
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / metabolism*
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / pathology
  • RNA Interference

Substances

  • 3' Untranslated Regions
  • MIRN204 microRNA, human
  • MicroRNAs
  • NF-kappa B
  • IRAK1 protein, human
  • Interleukin-1 Receptor-Associated Kinases
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9