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

Gianfranco Mattia, M. Cristina Errico, Federica Felicetti, Marina Petrini, Lisabianca Bottero, Luisa Tomasello, Paolo Romania, Alessandra Boe, Patrizia Segnalini, Antonio di Virgilio, Mario P. Colombo, Alessandra Carè

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)953-965
Number of pages13
JournalPigment Cell and Melanoma Research
Volume24
Issue number5
DOIs
Publication statusPublished - Oct 2011

Keywords

  • ETS-1
  • Melanoma
  • MicroRNA-222
  • Tumor progression

ASJC Scopus subject areas

  • Dermatology
  • Oncology
  • Biochemistry, Genetics and Molecular Biology(all)

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