title: Defective RAGE activity in embryonal rhabdomyosarcoma cells results in high PAX7 levels that sustain migration and invasiveness.
abstract: Rhabdomyosarcoma is a muscle-derived malignant tumor mainly affecting children. The most frequent variant, embryonal rhabdomyosarcoma (ERMS) is characterized by overexpression of the transcription factor, PAX7 which prevents ERMS cells from exiting the cell cycle and terminally differentiating. However, a role for PAX7 in the invasive properties of ERMS cells has not been investigated in detail thus far. Here we show that ectopic expression of receptor for advanced glycation end-products (RAGE) in human ERMS cells results in the activation of a RAGE/myogenin axis which downregulates PAX7 by transcriptional and post-translational mechanisms, as in normal myoblasts, and reduces metastasis formation. High PAX7 sustains migration and invasiveness in ERMS cells by upregulating EPHA3 and EFNA1 and downregulating NCAM1 thus decreasing the neural cell adhesion molecule (NCAM)/polysialylated-NCAM ratio. Microarray gene expression analysis shows that compared with the RAGE(-ve) TE671/WT cells and similarly to primary human myoblasts, TE671/RAGE cells show upregulation of genes involved in muscle differentiation and cell adhesion, and downregulation of cell migration related and major histocompatibility complex class I genes. Our data reveal a link between PAX7 and metastasis occurrence in ERMSs, and support a role for the RAGE/myogenin axis in metastasis suppression. Thus, low RAGE expression in ERMS primary tumors may be predictive of metastatic behavior.
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy, Interuniversity Institute of Myology (IIM), Italy and.
authors.forename: Sara
authors.initials: S
authors.lastname: Chiappalupi
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy, Interuniversity Institute of Myology (IIM), Italy and.
authors.forename: Francesca
authors.initials: F
authors.lastname: Riuzzi
authors.affiliation: Interuniversity Institute of Myology (IIM), Italy and Department of Neuroscience and Imaging, CeSI, University G. d'Annunzio Chieti-Pescara, 66013 Chieti, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Fulle
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy, Interuniversity Institute of Myology (IIM), Italy and.
authors.forename: Rosario
authors.initials: R
authors.lastname: Donato
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy, Interuniversity Institute of Myology (IIM), Italy and guglielmo.sorci@unipg.it.
authors.forename: Guglielmo
authors.initials: G
authors.lastname: Sorci
mesh_terms: D000818:Animals; D019002:CD56 Antigen / Q000235:genetics; D045744:Cell Line, Tumor / Q000187:drug effects; D002465:Cell Movement / Q000235:genetics; D036382:Ephrin-A1 / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D051379:Mice; D008817:Mice, Mutant Strains; D008819:Mice, Nude; D032446:Myoblasts / Q000473:pathology; D018008:Myogenin / Q000378:metabolism; D051763:PAX7 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D000067759:Receptor for Advanced Glycation End Products; D036121:Receptor, EphA3; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D018233:Rhabdomyosarcoma, Embryonal / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D019002:CD56 Antigen; D036382:Ephrin-A1; D007976:Leupeptins; D018008:Myogenin; C522918:NCAM1 protein, human; D051763:PAX7 Transcription Factor; C497321:PAX7 protein, human; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; C491718:EPHA3 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D036121:Receptor, EphA3; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde