Upregulation of miR-504-3p is associated with favorable prognosis of acute myeloid leukemia and may serve as a tumor suppressor by targeting MTHFD2

Eur Rev Med Pharmacol Sci. 2019 Feb;23(3):1203-1213. doi: 10.26355/eurrev_201902_17013.


Objective: Deregulated expression of miRNAs contributes to the development of acute myeloid leukemia (AML). miR-504-3p, one of these miRNAs, has been found have upregulated expression in various human malignancies. Our present study aimed to detect the expression of miR-504-3p and its biological effect in AML.

Patients and methods: Real-time quantitative PCR was applied to evaluate the expression level of miR-504-3p in AML cell lines and the serum from AML cases. The correlations between miR-504-3p and AML patients' clinicopathological characteristics, as well as AML patients' overall survival, were statistically assessed. Moreover, we investigated the effect of miR-504-3p knockdown on AML cells by CCK-8, Transwell assays and flow cytometry, in vitro. The Western blot, RT-PCR and luciferase reporter assay were performed to evaluate the relationship between miR-504-3p and its downstream target genes. Finally, the biological function of MTHFD2 was also analyzed.

Results: The expression levels of miR-504-3p were significantly down-regulated in the serum of AML patients and cell lines, and its low expression was positively associated with advanced clinical stages and poor prognosis of AML patients. Functional assays indicated that overexpression of miR-504-3p leads to AML cell growth arrest, invasion and migration inhibition, and elevated rates of apoptosis. We also found that miR-504-3p regulated the expression of MTHFD2 by binding to its 3'-UTR, and knockdown of MTHFD2 significantly suppressed AML cells proliferation, migration and invasion, and promoted apoptosis.

Conclusions: Our findings provide important evidence that supports the role of miR-504-3p as a tumor suppressor in AML via the inhibition of MTHFD2 expression.

MeSH terms

  • 3' Untranslated Regions
  • Aminohydrolases / economics*
  • Apoptosis / genetics
  • Case-Control Studies
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Gene Expression Regulation, Neoplastic*
  • Genes, Tumor Suppressor*
  • HL-60 Cells
  • Humans
  • Leukemia, Myeloid, Acute / genetics*
  • Leukemia, Myeloid, Acute / mortality
  • Leukemia, Myeloid, Acute / pathology
  • Methylenetetrahydrofolate Dehydrogenase (NADP) / economics*
  • MicroRNAs / genetics*
  • Multifunctional Enzymes / economics*
  • Survival Analysis
  • THP-1 Cells
  • Up-Regulation


  • 3' Untranslated Regions
  • MIRN504 microRNA, human
  • MTHFD2 protein, human
  • MicroRNAs
  • Multifunctional Enzymes
  • Methylenetetrahydrofolate Dehydrogenase (NADP)
  • Aminohydrolases