miR-181a down-regulates MAP2K1 to enhance adriamycin sensitivity in leukemia HL-60 cells

Eur Rev Med Pharmacol Sci. 2019 Mar;23(6):2497-2504. doi: 10.26355/eurrev_201903_17397.

Abstract

Objective: MAPK kinase 1 (MEK1), also known as MAP2K1, plays a role in activating extra-cellular signal-regulated protein kinase/mitogen-activated protein kinase (ERK/MAPK) signaling pathway to regulate cell proliferation and apoptosis. The abnormal expression of MAP2K1 is associated with leukemia. Bioinformatics analysis showed the targeted relationship between microRNA-181a (miR-181a) and the 3'-UTR of MAP2K1. This study aimed to investigate the role of miR-181a in regulating MAP2K1 expression, the effects on leukemic cell proliferation, apoptosis, and adriamycin (ADM) resistance.

Materials and methods: Dual luciferase reporter gene assay was applied to confirm the targeted relationship between miR-181a and MAP2K1. ADM resistant cell line HL-60/ADM was established. MiR-181a and MAP2K1 expressions were detected. HL-60/ADM cells were cultured in vitro and divided into two groups, including microRNA-Normal control (miR-NC) group and miR-181a mimic group. MAP2K1, phosphorylated MAP2K1 (p-MAP2K1), and phosphorylated ERK (p-ERK) protein expressions were tested. Cell apoptosis was assessed with flow cytometry. Cell proliferation was determined using EdU staining.

Results: There is a targeted regulatory relationship between miR-181a and MAP2K1 mRNA. miR-181a expression was significantly lower, while MAP2K1 mRNA and protein expressions were markedly higher in HL-60/ADM cells than HL-60 cells (p<0.05). Transfection of miR-181a mimic markedly reduced expressions of MAP2K1, p-MAP2K1, and p-ERK in HL-60/ADM cells, enhanced cell apoptosis, and weakened cell proliferation compared to miR-NC (p<0.05).

Conclusions: MiR-181a reduction and MAP2K1 elevation were related to ADM resistance in leukemia cells. Up-regulation of miR-181a expression inhibited leukemia cell proliferation, induced apoptosis, and reduced ADM resistance via targeting MAP2K1 expression and ERK/MAPK signaling pathway.

Publication types

  • Retracted Publication

MeSH terms

  • 3' Untranslated Regions
  • Cell Proliferation
  • Cell Survival
  • Down-Regulation
  • Doxorubicin / pharmacology*
  • Drug Resistance, Neoplasm*
  • Gene Expression Regulation, Neoplastic
  • HL-60 Cells
  • Humans
  • Leukemia, Promyelocytic, Acute / drug therapy
  • Leukemia, Promyelocytic, Acute / genetics*
  • MAP Kinase Kinase 1 / genetics*
  • MicroRNAs / genetics*

Substances

  • 3' Untranslated Regions
  • MIrn181 microRNA, human
  • MicroRNAs
  • Doxorubicin
  • MAP Kinase Kinase 1
  • MAP2K1 protein, human