Deep sequencing reveals a novel miR-22 regulatory network with therapeutic potential in rhabdomyosarcoma

Francesca Bersani, Marcello Francesco Lingua, Deborah Morena, Valentina Foglizzo, Silvia Miretti, Letizia Lanzetti, Giovanna Carrà, Alessandro Morotti, Ugo Ala, Paolo Provero, Roberto Chiarle, Samuel Singer, Marc Ladanyi, Thomas Tuschl, Carola Ponzetto, Riccardo Taulli

Research output: Contribution to journalArticle

Abstract

Current therapeutic options for the pediatric cancer rhabdomyosarcoma have not improved significantly, especially for metastatic rhabdomyosarcoma. In the current work, we performed a deep miRNA profiling of the three major human rhabdomyosarcoma subtypes, along with cell lines and normal muscle, to identify novel molecular circuits with therapeutic potential. The signature we determined could discriminate rhabdomyosarcoma from muscle, revealing a subset of muscle-enriched miRNA (myomiR), including miR-22, which was strongly underexpressed in tumors. miR-22 was physiologically induced during normal myogenic differentiation and was transcriptionally regulated by MyoD, confirming its identity as a myomiR. Once introduced into rhabdomyosarcoma cells, miR-22 decreased cell proliferation, anchorage-independent growth, invasiveness, and promoted apoptosis. Moreover, restoring miR-22 expression blocked tumor growth and prevented tumor dissemination in vivo. Gene expression profiling analysis of miR-22-expressing cells suggested TACC1 and RAB5B as possible direct miR-22 targets. Accordingly, loss- and gain-of-function experiments defined the biological relevance of these genes in rhabdomyosarcoma pathogenesis. Finally, we demonstrated the ability of miR-22 to intercept and overcome the intrinsic resistance to MEK inhibition based on ERBB3 upregulation. Overall, our results identified a novel miR-22 regulatory network with critical therapeutic implications in rhabdomyosarcoma.

Original languageEnglish
Pages (from-to)6095-6106
Number of pages12
JournalCancer Research
Volume76
Issue number20
DOIs
Publication statusPublished - Oct 15 2016

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Bersani, F., Lingua, M. F., Morena, D., Foglizzo, V., Miretti, S., Lanzetti, L., Carrà, G., Morotti, A., Ala, U., Provero, P., Chiarle, R., Singer, S., Ladanyi, M., Tuschl, T., Ponzetto, C., & Taulli, R. (2016). Deep sequencing reveals a novel miR-22 regulatory network with therapeutic potential in rhabdomyosarcoma. Cancer Research, 76(20), 6095-6106. https://doi.org/10.1158/0008-5472.CAN-16-0709