MicroRNA expression profiling in human ovarian cancer: miR-214 induces cell survival and cisplatin resistance by targeting PTEN

Cancer Res. 2008 Jan 15;68(2):425-33. doi: 10.1158/0008-5472.CAN-07-2488.

Abstract

MicroRNAs (miRNA) represent a novel class of genes that function as negative regulators of gene expression. Recently, miRNAs have been implicated in several cancers. However, aberrant miRNA expression and its clinicopathologic significance in human ovarian cancer have not been well documented. Here, we show that several miRNAs are altered in human ovarian cancer, with the most significantly deregulated miRNAs being miR-214, miR-199a*, miR-200a, miR-100, miR-125b, and let-7 cluster. Further, we show the frequent deregulation of miR-214, miR-199a*, miR-200a, and miR-100 in ovarian cancers. Significantly, miR-214 induces cell survival and cisplatin resistance through targeting the 3'-untranslated region (UTR) of the PTEN, which leads to down-regulation of PTEN protein and activation of Akt pathway. Inhibition of Akt using Akt inhibitor, API-2/triciribine, or introduction of PTEN cDNA lacking 3'-UTR largely abrogates miR-214-induced cell survival. These findings indicate that deregulation of miRNAs is a recurrent event in human ovarian cancer and that miR-214 induces cell survival and cisplatin resistance primarily through targeting the PTEN/Akt pathway.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antineoplastic Agents / therapeutic use
  • Apoptosis / genetics
  • Base Sequence
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Cisplatin / therapeutic use*
  • Drug Resistance, Neoplasm / genetics*
  • Female
  • Gene Expression Profiling*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • MicroRNAs / genetics*
  • MicroRNAs / physiology*
  • Molecular Sequence Data
  • Oligonucleotide Array Sequence Analysis*
  • Oncogene Protein v-akt / antagonists & inhibitors
  • Oncogene Protein v-akt / metabolism
  • Ovarian Neoplasms / genetics*
  • PTEN Phosphohydrolase / genetics*
  • Ribonucleosides / pharmacology
  • Sequence Homology, Nucleic Acid
  • Signal Transduction / genetics
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • MicroRNAs
  • Ribonucleosides
  • triciribine
  • Oncogene Protein v-akt
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • Cisplatin