Novel microRNA Regulatory Network Has Important Therapeutic Implications in Rhabdomyosarcoma Interview with:
Riccardo Taulli, PhD
Assistant Professor of Biochemistry
Dept. of Oncology, University of Turin
Via Santena 5, 10126
Torino, Italy What is the background for this study?

Response: Rhabdomyosarcoma is a muscle-derived pediatric cancer for which therapeutic options have not improved significantly over the past decades, especially for its metastatic form. MicroRNAs are small regulatory molecules that control gene expression at the post-transcriptional level, fine tuning a wide number of cellular mechanisms, processes and behaviors. In our work, we underwent a large microRNA isolation and sequencing effort using human samples of the three major rhabdomyosarcoma subtypes, along with cell lines and normal muscle, to identify novel molecular circuits with therapeutic potential. What are the main findings?

Response: Our analysis uncovered a microRNA signature that was able to discriminate rhabdomyosarcoma from muscle, revealing a subset of muscle-enriched microRNAs (myomiR), including miR-22, which was strongly underexpressed in tumors. Conversely, we found that miR-22 physiologically increased during normal muscle differentiation upon regulation by MyoD, one of the most potent muscle-specific transcription factors, thus confirming its identity as a myomiR. Remarkably, rhabdomyosarcoma cells engineered to express this “lost” microRNA displayed a significant reduction of many of their tumorigenic properties, such as abnormal cell proliferation, anchorage-independent growth, invasiveness, and resistance to programmed cell death. Moreover, restoring miR-22 expression blocked tumor growth and prevented tumor dissemination in mice. We also identified two possible targets of miR-22, TACC1 and RAB5B, and proved their biological relevance in rhabdomyosarcoma pathogenesis.

Finally, we demonstrated in vitro the ability of miR-22 to overcome resistance to therapeutic MEK inhibition based on ERBB3 upregulation. What should readers take away from your report?

Response: Overall, our results identified a novel microRNA regulatory network with important therapeutic implications in rhabdomyosarcoma. What recommendations do you have for future research as a result of this study?

Response: It would be desirable to investigate the possibility of systemic mir-22 administration within a combination therapy regimen in a rhabdomyosarcoma mouse model. This would help understanding the actual potential of this and other microRNAs in opposing the occurrence of resistance mechanisms, which currently represent one of the main challenges to targeted therapeutic approaches, one step further than traditional and more toxic chemotherapy treatments. Is there anything else you would like to add?

Response: Collaboration among laboratories with different backgrounds and skills was key in achieving these results. Thank you for your contribution to the community.


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, SamuelSinger, Marc Ladanyi, Thomas Tuschl, Carola Ponzetto and Riccardo Taulli
Cancer Res August 28 2016 DOI: 10.1158/0008-5472.CAN-16-0709

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