title: The RhoE/ROCK/ARHGAP25 signaling pathway controls cell invasion by inhibition of Rac activity.
abstract: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of skeletal muscle origin in children and adolescents. Among RMS subtypes, alveolar rhabdomyosarcoma (ARMS), which is characterized by the presence of the PAX3-FOXO1A or PAX7-FOXO1A chimeric oncogenic transcription factor, is associated with poor prognosis and a strong risk of metastasis compared with the embryonal subtype (ERMS). To identify molecular pathways involved in ARMS aggressiveness, we first characterized the migratory behavior of cell lines derived from ARMS and ERMS biopsies using a three-dimensional spheroid cell invasion assay. ARMS cells were more invasive than ERMS cells and adopted an ellipsoidal morphology to efficiently invade the extracellular matrix. Moreover, the invasive potential of ARMS cells depended on ROCK activity, which is regulated by the GTPase RhoE. Specifically, RhoE expression was low in ARMS biopsies, and its overexpression in ARMS cells reduced their invasion potential. Conversely, ARHGAP25, a GTPase-activating protein for Rac, was up-regulated in ARMS biopsies. Moreover, we found that ARHGAP25 inhibits Rac activity downstream of ROCKII and is required for ARMS cell invasion. Our results indicate that the RhoE/ROCK/ARHGAP25 signaling pathway promotes ARMS invasive potential and identify these proteins as potential therapeutic targets for ARMS treatment.
authors.affiliation: Université de Montpellier, CRBM, CNRS, UMR 5237, 34293 Montpellier, France sylvie.thuault@inserm.fr cecile.gauthier@crbm.cnrs.fr.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Thuault
authors.affiliation: Université de Montpellier, CRBM, CNRS, UMR 5237, 34293 Montpellier, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Comunale
authors.affiliation: Université de Montpellier, CRBM, CNRS, UMR 5237, 34293 Montpellier, France.
authors.forename: Jessy
authors.initials: J
authors.lastname: Hasna
authors.affiliation: Université de Montpellier, CRBM, CNRS, UMR 5237, 34293 Montpellier, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Fortier
authors.affiliation: Université de Montpellier, CRBM, CNRS, UMR 5237, 34293 Montpellier, France.
authors.forename: Damien
authors.initials: D
authors.lastname: Planchon
authors.affiliation: Ligue Nationale Contre le Cancer, Cartes d'Identité des Tumeurs, 75013 Paris, France.
authors.forename: Nabila
authors.initials: N
authors.lastname: Elarouci
authors.affiliation: Ligue Nationale Contre le Cancer, Cartes d'Identité des Tumeurs, 75013 Paris, France.
authors.forename: Aurélien
authors.initials: A
authors.lastname: De Reynies
authors.affiliation: Université de Montpellier, CRBM, CNRS, UMR 5237, 34293 Montpellier, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Bodin
authors.affiliation: Université de Montpellier, CRBM, CNRS, UMR 5237, 34293 Montpellier, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Blangy
authors.affiliation: Université de Montpellier, CRBM, CNRS, UMR 5237, 34293 Montpellier, France sylvie.thuault@inserm.fr cecile.gauthier@crbm.cnrs.fr.
authors.forename: Cécile
authors.initials: C
authors.lastname: Gauthier-Rouvière
mesh_terms: D002454:Cell Differentiation; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D051858:Forkhead Transcription Factors / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000235:genetics* / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D018482:Muscle, Skeletal / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000378:metabolism; D012208:Rhabdomyosarcoma; D018232:Rhabdomyosarcoma, Alveolar / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D020744:rac GTP-Binding Proteins / Q000037:antagonists & inhibitors; D020741:rho GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: C497035:ARHGAP25 protein, human; D051858:Forkhead Transcription Factors; D020690:GTPase-Activating Proteins; D015514:Oncogene Proteins, Fusion; C515851:ROCK1 protein, human; D054460:rho-Associated Kinases; C508705:RND3 protein, human; D020744:rac GTP-Binding Proteins; D020741:rho GTP-Binding Proteins