MicroRNA-519d-3p Inhibits Proliferation and Promotes Apoptosis by Targeting HIF-2α in Cervical Cancer Under Hypoxic Conditions

Oncol Res. 2018 Aug 23;26(7):1055-1062. doi: 10.3727/096504018X15152056890500. Epub 2018 Jan 10.


HIF-2α knockdown inhibits proliferation, arrests the cell cycle, and promotes apoptosis and autophagy under hypoxic conditions in cervical cancer. However, the upstream regulatory mechanism of HIF-2α expression is unclear. MicroRNAs (miRNAs) degrade target mRNAs by binding to the 3'-untranslated region of mRNAs. In this study, we investigated the role of miRNAs in the regulation of HIF-2α expression in cervical cancer under hypoxic conditions. miRNAs regulating HIF-2α expression were predicted using TargetScan and miRanda and were determined in cervical cancer under hypoxic conditions by qRT-PCR. Additionally, the targeted regulation of HIF-2α by miR-519d-3p was evaluated by Western blot and luciferase reporter assays. Effects of miR-519d-3p and HIF-2α on cell proliferation, cell cycle, and apoptosis were analyzed by CCK-8 and flow cytometry assays, respectively. miR-106a-5p, miR-17-5p, miR-519d-3p, miR-526b-3p, and miR-20b-5p are potentially regulatory miRNAs that bound to the HIF-2α 3'-untranslated region as per TargetScan and miRanda predictions. Expression of the five miRNAs was inhibited in HeLa cells under hypoxic conditions compared to normoxic conditions, and the expression of miR-519d-3p was lower than that of other miRNAs. Luciferase reporter assays showed that HIF-2α was a target of miR-519d-3p. Additionally, miR-519d-3p overexpression inhibited cell proliferation, arrested the cell cycle transition from the G1 stage to the S stage, and promoted cell apoptosis under hypoxic conditions in cervical cancer. HIF-2α overexpression partially reversed the effect of miR-519d-3p. In conclusion, miR-519d-3p overexpression suppressed proliferation, inhibited the cell cycle, and promoted apoptosis of HeLa cells by targeting HIF-2α under hypoxic conditions.

MeSH terms

  • Apoptosis*
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism*
  • Cell Cycle
  • Cell Proliferation*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Hypoxia*
  • MicroRNAs / genetics*
  • Signal Transduction
  • Tumor Cells, Cultured
  • Uterine Cervical Neoplasms / genetics
  • Uterine Cervical Neoplasms / metabolism
  • Uterine Cervical Neoplasms / pathology*


  • Basic Helix-Loop-Helix Transcription Factors
  • Biomarkers, Tumor
  • MIRN519 microRNA, human
  • MicroRNAs
  • endothelial PAS domain-containing protein 1