In Vitro and in Vivo Anti-tumor Activity of miR-221/222 inhibitors in multiple myeloma

Maria Teresa Di Martino, Annamaria Gullà, Maria Eugenia Gallo Cantafio, Marta Lionetti, Emanuela Leone, Nicola Amodio, Pietro Hiram Guzzi, Umberto Foresta, Francesco Conforti, Mario Cannataro, Antonino Neri, Antonio Giordano, Pierosandro Tagliaferri, Pierfrancesco Tassone

Research output: Contribution to journalArticle

Abstract

A rising body of evidence suggests that silencing microRNAs (miRNAs) with oncogenic potential may represent a successful therapeutic strategy for human cancer. We investigated the therapeutic activity of miR-221/222 inhibitors against human multiple myeloma (MM) cells. Enforced expression of miR-221/222 inhibitors triggered in vitro anti-proliferative effects and up-regulation of canonic miR-221/222 targets, including p27Kip1, PUMA, PTEN and p57Kip2, in MM cells highly expressing miR-221/222. Conversely, transfection of miR-221/222 mimics increased S-phase and down-regulated p27Kip1 protein expression in MM with low basal miR-221/222 levels. The effects of miR-221/222 inhibitors was also evaluated in MM xenografts in SCID/ NOD mice. Significant anti-tumor activity was achieved in xenografted mice by the treatment with miR-221/222 inhibitors, together with up-regulation of canonic protein targets in tumors retrieved from animals. These findings provide proof of principle that silencing the miR-221/222 cluster exerts significant therapeutic activity in MM cells with high miR-221/222 level of expression, which mostly occurs in TC2 and TC4 MM groups. These findings suggest that MM genotyping may predict the therapeutic response. All together our results support a framework for clinical development of miR-221/222 inhibitors-based therapeutic strategy in this still incurable disease.

Original languageEnglish
Pages (from-to)242-255
Number of pages14
JournalOncotarget
Volume4
Issue number2
Publication statusPublished - 2013

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Keywords

  • Microrna
  • Mir-221
  • Mir-222
  • Mirna
  • Multiple myeloma
  • Plasma cell leukemia

ASJC Scopus subject areas

  • Oncology

Cite this

Di Martino, M. T., Gullà, A., Cantafio, M. E. G., Lionetti, M., Leone, E., Amodio, N., Guzzi, P. H., Foresta, U., Conforti, F., Cannataro, M., Neri, A., Giordano, A., Tagliaferri, P., & Tassone, P. (2013). In Vitro and in Vivo Anti-tumor Activity of miR-221/222 inhibitors in multiple myeloma. Oncotarget, 4(2), 242-255.