Constitutive activation of the ETS-1-miR-222 circuitry in metastatic melanoma

Pigment Cell Melanoma Res. 2011 Oct;24(5):953-65. doi: 10.1111/j.1755-148X.2011.00881.x.


MicroRNAs-221 and -222 are highly upregulated in several solid tumors, including melanomas. We demonstrate that the proto-oncogene ETS-1, involved in the pathogenesis of cancers of different origin, is a transcriptional regulator of miR-222 by direct binding to its promoter region. Differently from 293FT cells or early stage melanomas, where unphosphorylated ETS-1 represses miR-222 transcription, in metastatic melanoma the constitutively Thr-38 phosphorylated fraction of ETS-1 induces miR-222. Despite its stepwise decreased expression along with melanoma progression, the oncogenic activity of ETS-1 relies on its RAS/RAF/ERK-dependent phosphorylation status more than on its total amount. To close the loop, we demonstrate ETS-1 as a direct target of miR-222, but not miR-221, showing the novel option of their uncoupled functions. In addition, a spatial redistribution of ETS-1 protein from the nucleus to the cytoplasm is also evidenced in advanced melanoma cells. Finally, in vivo studies confirmed the contribution of miR-222 to the increased invasive potential obtained by ETS- silencing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Down-Regulation / drug effects
  • Gene Expression Regulation, Neoplastic* / drug effects
  • Humans
  • Melanocytes / metabolism
  • Melanocytes / pathology
  • Melanoma / genetics*
  • Melanoma / pathology*
  • Mice
  • Mice, Nude
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Neoplasm Metastasis
  • Phosphorylation / drug effects
  • Phosphothreonine / metabolism
  • Proto-Oncogene Protein c-ets-1 / genetics*
  • Proto-Oncogene Protein c-ets-1 / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / genetics*
  • Skin Neoplasms / genetics*
  • Skin Neoplasms / pathology
  • Tetradecanoylphorbol Acetate / pharmacology
  • Transcription, Genetic / drug effects


  • ETS1 protein, human
  • MIRN221 microRNA, human
  • MIRN222 microRNA, human
  • MicroRNAs
  • Proto-Oncogene Protein c-ets-1
  • Phosphothreonine
  • Tetradecanoylphorbol Acetate