MiRNA-543 promotes osteosarcoma cell proliferation and glycolysis by partially suppressing PRMT9 and stabilizing HIF-1α protein

Oncotarget. 2017 Jan 10;8(2):2342-2355. doi: 10.18632/oncotarget.13672.

Abstract

Osteosarcoma (OS) is the most common primary bone tumor, occurring frequently in adolescents and possessing a high malignant severity. MicroRNAs play critical roles during OS development. Thus, elucidation of the involvement of specific microRNAs in the development of OS may provide novel therapeutic targets for OS treatment. Here, we showed that in the OS specimens from patients, the levels of miR-543 were significantly increased whereas the levels of PRMT9 were significantly decreased, compared to the paired normal bone tissue. Moreover, miR-543 and PRMT9 inversely correlated in the OS cell lines. Bioinformatics analyses predicted that miR-543 may target the 3'-UTR of PRMT9 mRNA to inhibit its translation, which was confirmed by luciferase-reporter assay. MiR-543 promoted OS cell proliferation in vitro and in vivo. Mechanistically, miR-543 inhibited PRMT9-enhanced cell oxidative phosphorylation, while miR-543 depletion promoted PRMT9-increased HIF-1α instability and inhibited glycolysis in OS cells. Clinically, miR-543 expression was negatively correlated with PRMT9 expression in OS tissues. Together, our data provide important evidence for glycolysis in OS development, and suggest that targeting glycolytic pathway through miR-543/PRMT9/HIF-1α axis may represent a potential therapeutic strategy to eradicate OS cells.

Keywords: HIF-1α; PRMT9; glycolysis; miRNA-543; osteosarcoma.

MeSH terms

  • Adolescent
  • Animals
  • Bone Neoplasms / genetics
  • Bone Neoplasms / metabolism
  • Bone Neoplasms / pathology*
  • Cell Proliferation / genetics*
  • Child
  • F-Box Proteins / genetics*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Glycolysis / genetics*
  • HEK293 Cells
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics*
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Male
  • Mice
  • Mice, Nude
  • MicroRNAs / physiology*
  • Osteosarcoma / genetics
  • Osteosarcoma / metabolism
  • Osteosarcoma / pathology*
  • Protein-Arginine N-Methyltransferases / genetics*
  • RNA Stability / genetics
  • Signal Transduction / genetics
  • Tumor Cells, Cultured

Substances

  • F-Box Proteins
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • MIRN543 microRNA, human
  • MicroRNAs
  • FBXO11 protein, human
  • Protein-Arginine N-Methyltransferases