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Carcinogenesis. 2014 Oct;35(10):2382-92. doi: 10.1093/carcin/bgu176. Epub 2014 Aug 14.

Defective RAGE activity in embryonal rhabdomyosarcoma cells results in high PAX7 levels that sustain migration and invasiveness.

Author information

1
Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy, Interuniversity Institute of Myology (IIM), Italy and.
2
Interuniversity Institute of Myology (IIM), Italy and Department of Neuroscience and Imaging, CeSI, University G. d'Annunzio Chieti-Pescara, 66013 Chieti, Italy.
3
Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy, Interuniversity Institute of Myology (IIM), Italy and guglielmo.sorci@unipg.it.

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.

PMID:
25123133
DOI:
10.1093/carcin/bgu176
[Indexed for MEDLINE]
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