title: Let-7a is a direct EWS-FLI-1 target implicated in Ewing's sarcoma development.
abstract: Ewing's sarcoma family tumors (ESFT) are the second most common bone malignancy in children and young adults, characterized by unique chromosomal translocations that in 85% of cases lead to expression of the EWS-FLI-1 fusion protein. EWS-FLI-1 functions as an aberrant transcription factor that can both induce and suppress members of its target gene repertoire. We have recently demonstrated that EWS-FLI-1 can alter microRNA (miRNA) expression and that miRNA145 is a direct EWS-FLI-1 target whose suppression is implicated in ESFT development. Here, we use miRNA arrays to compare the global miRNA expression profile of human mesenchymal stem cells (MSC) and ESFT cell lines, and show that ESFT display a distinct miRNA signature that includes induction of the oncogenic miRNA 17-92 cluster and repression of the tumor suppressor let-7 family. We demonstrate that direct repression of let-7a by EWS-FLI-1 participates in the tumorigenic potential of ESFT cells in vivo. The mechanism whereby let-7a expression regulates ESFT growth is shown to be mediated by its target gene HMGA2, as let-7a overexpression and HMGA2 repression both block ESFT cell tumorigenicity. Consistent with these observations, systemic delivery of synthetic let-7a into ESFT-bearing mice restored its expression in tumor cells, decreased HMGA2 expression levels and resulted in ESFT growth inhibition in vivo. Our observations provide evidence that deregulation of let-7a target gene expression participates in ESFT development and identify let-7a as promising new therapeutic target for one of the most aggressive pediatric malignancies.
authors.affiliation: Faculty of Biology and Medicine, Institute of Pathology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland.
authors.forename: Claudio
authors.initials: C
authors.lastname: De Vito
authors.forename: Nicolo
authors.initials: N
authors.lastname: Riggi
authors.forename: Mario-Luca
authors.initials: ML
authors.lastname: Suvà
authors.forename: Michalina
authors.initials: M
authors.lastname: Janiszewska
authors.forename: Janine
authors.initials: J
authors.lastname: Horlbeck
authors.forename: Karine
authors.initials: K
authors.lastname: Baumer
authors.forename: Paolo
authors.initials: P
authors.lastname: Provero
authors.forename: Ivan
authors.initials: I
authors.lastname: Stamenkovic
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D025743:HMGA2 Protein / Q000235:genetics / Q000378:metabolism; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D011230:Precancerous Conditions / Q000235:genetics / Q000473:pathology*; D051789:Proto-Oncogene Protein c-fli-1 / Q000378:metabolism*; D034802:RNA-Binding Protein EWS / Q000378:metabolism*; D012512:Sarcoma, Ewing / Q000235:genetics / Q000473:pathology*
chemical_list: C106031:EWS-FLI fusion protein; D025743:HMGA2 Protein; D035683:MicroRNAs; D015514:Oncogene Proteins, Fusion; D051789:Proto-Oncogene Protein c-fli-1; D034802:RNA-Binding Protein EWS; C487931:mirnlet7 microRNA, human