Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma, arising from muscle precursor cells. TE671 RMS cells, like other RMS cell lines, show inability to complete the differentiation program despite the expression of muscle-specific regulatory proteins. However, persistent activation of p38 MAPK in RMS cells results in growth arrest and myogenic differentiation (Genes Dev 14, 574-584), implying that defective activation of p38 MAPK might be one cause of inability of TE671 cells to escape from the cell cycle and activate the myogenic program. RAGE (receptor for advanced glycation end products), activated by its ligand, amphoterin (HMGB1), stimulates myogenesis via a Cdc42-Rac1-MKK6-p38 MAPK pathway (Mol Cell Biol 24 (2004) 4880-4894), and functional inactivation of RAGE in myoblasts results in reduced myogenesis, increased proliferation and tumor formation in vivo (J Biol Chem 281 (2006) 8242-8253). We show here that TE671 RMS cells, which do not express RAGE, can be induced to differentiate upon transfection with RAGE (TE671/RAGE cells) but not a RAGE mutant lacking the transducing domain (RAGEDcyto) (TE671/RAGEDcyto cells) via a Cdc42-Rac1-MKK6-p38 MAPK pathway, and that TE671/RAGE cell differentiation depends on RAGE ligation by amphoterin. TE671/RAGE cells also show reduced proliferation, migration and invasiveness and increased apoptosis, volume and adhesiveness in vitro, and generate smaller tumors with a lower incidence in vivo compared with wild-type TE671 cells. Two other RMS cell lines, CCA and RMZ-RC2, that do express RAGE, show an inverse relationship between the level of RAGE expression and invasiveness in vitro, and show reduced myogenic potential and enhanced invasiveness in vitro when transfected with RAGEDcyto. These data support the proposal that RAGE ligation by amphoterin might play a physiological role in myogenesis and suggest that deregulation of RAGE expression in myoblasts might concur in rhabdomyosarcomagenesis.

Enforced expression of RAGE in rhabdomyosarcoma cells result in reduced proliferation, migration, and invasiveness in vitro, activation of a myogenic program, and reduced tumor growth in vivo.

RIUZZI, Francesca;SORCI, Guglielmo;DONATO, Rosario Francesco
2006

Abstract

Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma, arising from muscle precursor cells. TE671 RMS cells, like other RMS cell lines, show inability to complete the differentiation program despite the expression of muscle-specific regulatory proteins. However, persistent activation of p38 MAPK in RMS cells results in growth arrest and myogenic differentiation (Genes Dev 14, 574-584), implying that defective activation of p38 MAPK might be one cause of inability of TE671 cells to escape from the cell cycle and activate the myogenic program. RAGE (receptor for advanced glycation end products), activated by its ligand, amphoterin (HMGB1), stimulates myogenesis via a Cdc42-Rac1-MKK6-p38 MAPK pathway (Mol Cell Biol 24 (2004) 4880-4894), and functional inactivation of RAGE in myoblasts results in reduced myogenesis, increased proliferation and tumor formation in vivo (J Biol Chem 281 (2006) 8242-8253). We show here that TE671 RMS cells, which do not express RAGE, can be induced to differentiate upon transfection with RAGE (TE671/RAGE cells) but not a RAGE mutant lacking the transducing domain (RAGEDcyto) (TE671/RAGEDcyto cells) via a Cdc42-Rac1-MKK6-p38 MAPK pathway, and that TE671/RAGE cell differentiation depends on RAGE ligation by amphoterin. TE671/RAGE cells also show reduced proliferation, migration and invasiveness and increased apoptosis, volume and adhesiveness in vitro, and generate smaller tumors with a lower incidence in vivo compared with wild-type TE671 cells. Two other RMS cell lines, CCA and RMZ-RC2, that do express RAGE, show an inverse relationship between the level of RAGE expression and invasiveness in vitro, and show reduced myogenic potential and enhanced invasiveness in vitro when transfected with RAGEDcyto. These data support the proposal that RAGE ligation by amphoterin might play a physiological role in myogenesis and suggest that deregulation of RAGE expression in myoblasts might concur in rhabdomyosarcomagenesis.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11391/913905
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