title: Deep Sequencing Reveals a Novel miR-22 Regulatory Network with Therapeutic Potential in Rhabdomyosarcoma.
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. Cancer Res; 76(20); 6095-106. ©2016 AACR.
authors: Department of Oncology, University of Turin, Orbassano, Turin, Italy. CeRMS, Center for Experimental Research and Medical Studies, Turin, Italy.
authors: Francesca
authors: F
authors: Bersani
authors: Department of Oncology, University of Turin, Orbassano, Turin, Italy. CeRMS, Center for Experimental Research and Medical Studies, Turin, Italy.
authors: Marcello Francesco
authors: MF
authors: Lingua
authors: Department of Oncology, University of Turin, Orbassano, Turin, Italy. CeRMS, Center for Experimental Research and Medical Studies, Turin, Italy.
authors: Deborah
authors: D
authors: Morena
authors: Department of Oncology, University of Turin, Orbassano, Turin, Italy. CeRMS, Center for Experimental Research and Medical Studies, Turin, Italy.
authors: Valentina
authors: V
authors: Foglizzo
authors: Department of Veterinary Science, University of Turin, Grugliasco, Italy.
authors: Silvia
authors: S
authors: Miretti
authors: Department of Oncology, University of Turin, Orbassano, Turin, Italy. Candiolo Cancer Institute, Candiolo, Turin, Italy.
authors: Letizia
authors: L
authors: Lanzetti
authors: Department of Clinical and Biological Sciences, University of Turin, Orbassano, Italy.
authors: Giovanna
authors: G
authors: Carrà
authors: Department of Clinical and Biological Sciences, University of Turin, Orbassano, Italy.
authors: Alessandro
authors: A
authors: Morotti
authors: Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy.
authors: Ugo
authors: U
authors: Ala
authors: Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy.
authors: Paolo
authors: P
authors: Provero
authors: CeRMS, Center for Experimental Research and Medical Studies, Turin, Italy. Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy. Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.
authors: Roberto
authors: R
authors: Chiarle
authors: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors: Samuel
authors: S
authors: Singer
authors: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors: Marc
authors: M
authors: Ladanyi
authors: Department of RNA Molecular Biology, Howard Hughes Medical Institute, The Rockefeller University, New York, New York.
authors: Thomas
authors: T
authors: Tuschl
authors: Department of Oncology, University of Turin, Orbassano, Turin, Italy. CeRMS, Center for Experimental Research and Medical Studies, Turin, Italy. riccardo.taulli@unito.it carola.ponzetto@unito.it.
authors: Carola
authors: C
authors: Ponzetto
authors: Department of Oncology, University of Turin, Orbassano, Turin, Italy. CeRMS, Center for Experimental Research and Medical Studies, Turin, Italy. riccardo.taulli@unito.it carola.ponzetto@unito.it.
authors: Riccardo
authors: R
authors: Taulli
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D005260:Female; D005326:Fetal Proteins / Q000235:genetics / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000502:physiology*; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000502:physiology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D017570:MyoD Protein / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology; D011401:Promoter Regions, Genetic; D020893:Receptor, ErbB-3 / Q000235:genetics / Q000502:physiology; D012208:Rhabdomyosarcoma / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D020696:rab5 GTP-Binding Proteins / Q000235:genetics / Q000502:physiology
chemical_list: D005326:Fetal Proteins; C548375:MIRN22 microRNA, human; C526012:MIRN378 microRNA, human; D035683:MicroRNAs; D008869:Microtubule-Associated Proteins; D017570:MyoD Protein; D009687:Nuclear Proteins; C120584:TACC1 protein, human; C581292:ERBB3 protein, human; D020893:Receptor, ErbB-3; D020929:Mitogen-Activated Protein Kinase Kinases; C427755:RAB5C protein, human; D020696:rab5 GTP-Binding Proteins