miR-221&222 regulate TRAIL resistance and enhance tumorigenicity through PTEN and TIMP3 downregulation

Cancer Cell. 2009 Dec 8;16(6):498-509. doi: 10.1016/j.ccr.2009.10.014.


Lung and liver cancers are among the most deadly types of cancer. Despite improvements in treatment over the past few decades, patient survival remains poor, underlining the need for development of targeted therapies. MicroRNAs represent a class of small RNAs frequently deregulated in human malignancies. We now report that miR-221&222 are overexpressed in aggressive non-small cell lung cancer and hepatocarcinoma cells, as compared with less invasive and/or normal lung and liver cells. We show that miR-221&222, by targeting PTEN and TIMP3 tumor suppressors, induce TRAIL resistance and enhance cellular migration through the activation of the AKT pathway and metallopeptidases. Finally, we demonstrate that the MET oncogene is involved in miR-221&222 activation through the c-Jun transcription factor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Non-Small-Cell Lung / pathology
  • Down-Regulation / physiology*
  • Humans
  • Liver Neoplasms / pathology
  • MicroRNAs / physiology*
  • PTEN Phosphohydrolase / physiology*
  • TNF-Related Apoptosis-Inducing Ligand / physiology*
  • Tissue Inhibitor of Metalloproteinase-3 / physiology*


  • MIRN221 microRNA, human
  • MIRN222 microRNA, human
  • MicroRNAs
  • TIMP3 protein, human
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • Tissue Inhibitor of Metalloproteinase-3
  • PTEN Phosphohydrolase
  • PTEN protein, human