MicroRNA-221 targets PTEN to reduce the sensitivity of cervical cancer cells to gefitinib through the PI3K/Akt signaling pathway

Tumour Biol. 2016 Mar;37(3):3939-47. doi: 10.1007/s13277-015-4247-8. Epub 2015 Oct 19.


Patients with cervical cancer show minimal clinical response to the tyrosine kinase inhibitor gefitinib, which targets the epidermal growth factor receptor (EGFR). The molecular mechanisms underlying sensitivity to gefitinib are unknown. The purpose of this study was to investigate the possible mechanism by which microRNA-221 (miR-221) affects sensitivity to gefitinib. We showed that miR-221 expression was significantly increased in cervical cancer tissues compared with adjacent normal tissues. Upregulation of miR-221 expression in cervical cancer cells decreased PTEN expression levels, resulting in increased pAkt and BCL-2 expression. Importantly, gefitinib sensitivity was decreased by the upregulation of miR-221, which was blocked by pcDNA-PTEN co-transfection or by the phosphatidylinositol-3 kinase (PI3K) inhibitor LY294002. These data suggest that miR-221 can reduce the sensitivity of cervical cancer cells to gefitinib through the PTEN/PI3K/Akt signaling pathway. miR-221 represents a potential target to increase the sensitivity to gefitinib in cervical cancer treatment.

Keywords: Cervical cancer; Gefitinib; PTEN; miR-221.

MeSH terms

  • 3' Untranslated Regions / genetics
  • Antineoplastic Agents / pharmacology
  • Blotting, Western
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Chromones / pharmacology
  • Enzyme Inhibitors / pharmacology
  • Female
  • Gefitinib
  • HeLa Cells
  • Humans
  • MicroRNAs / genetics*
  • Morpholines / pharmacology
  • PTEN Phosphohydrolase / genetics*
  • PTEN Phosphohydrolase / metabolism
  • Phosphatidylinositol 3-Kinase / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Quinazolines / pharmacology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / drug effects
  • Uterine Cervical Neoplasms / genetics*
  • Uterine Cervical Neoplasms / metabolism
  • Uterine Cervical Neoplasms / pathology


  • 3' Untranslated Regions
  • Antineoplastic Agents
  • Chromones
  • Enzyme Inhibitors
  • MIRN221 microRNA, human
  • MicroRNAs
  • Morpholines
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins c-bcl-2
  • Quinazolines
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Phosphatidylinositol 3-Kinase
  • Proto-Oncogene Proteins c-akt
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • Gefitinib