title: Caveolin-1 promotes Ewing sarcoma metastasis regulating MMP-9 expression through MAPK/ERK pathway.
abstract: Ewing sarcoma (ES) is a bone and soft tissue sarcoma affecting mostly children and young adults. Caveolin-1 (CAV1) is a well-known target of EWS/FLI1, the main driver of ES, with an oncogenic role in ES. We have previously described how CAV1 is able to induce metastasis in ES via matrix metalloproteinase-9 (MMP-9). In the present study we showed how CAV1 silencing in ES reduced MEK1/2 and ERK1/2 phosphorylation. Accordingly, chemical inhibition of MEK1/2 resulted in reduction in MMP-9 expression and activity that correlated with reduced migration and invasion. IQ Motif Containing GTPase Activating Protein 1 (IQGAP1) silencing reduced MEK1/2 and ERK1/2 phosphorylation and MMP-9 expression. Furthermore, IQGAP1 silenced cells showed a marked decrease in their migratory and invasive capacity. We demonstrated that CAV1 and IQGAP1 localize in close proximity at the cellular edge, thus IQGAP1 could be the connecting node between CAV1 and MEK/ERK in ES metastatic phenotype. Analysis of the phosphorylation profile of CAV1-silenced cells showed a decrease of p-ribosomal protein S6 (RPS6). RPS6 can be phosphorylated by p90 ribosomal S6 kinases (RSK) proteins. CAV1-silenced cells showed reduced levels of p-RSK1 and treatment with U0126 provoked the same effect. Despite not affecting ERK1/2 and RPS6 phosphorylation status neither MMP-9 expression nor activity, RSK1 silencing resulted in a reduced migratory and invasive capacity in vitro and reduced incidence of metastases in vivo in a novel orthotopic model. The present work provides new insights into CAV1-driven metastatic process in ES unveiling novel key nodes.
authors.affiliation: Sarcoma Research Group, Institut d'Investigació Biomèdica de Bellvitge-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Lagares-Tena
authors.affiliation: Sarcoma Research Group, Institut d'Investigació Biomèdica de Bellvitge-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: García-Monclús
authors.affiliation: Sarcoma Research Group, Institut d'Investigació Biomèdica de Bellvitge-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Roser
authors.initials: R
authors.lastname: López-Alemany
authors.affiliation: Sarcoma Research Group, Institut d'Investigació Biomèdica de Bellvitge-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Olga
authors.initials: O
authors.lastname: Almacellas-Rabaiget
authors.affiliation: Sarcoma Research Group, Institut d'Investigació Biomèdica de Bellvitge-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Huertas-Martínez
authors.affiliation: Sarcoma Research Group, Institut d'Investigació Biomèdica de Bellvitge-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Sáinz-Jaspeado
authors.affiliation: Developmental Tumor Biology Laboratory, Hospital Sant Joan de Deu, Barcelona, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Mateo-Lozano
authors.affiliation: Pediatric Hematology/Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Rodríguez-Galindo
authors.affiliation: Sarcoma Research Group, Institut d'Investigació Biomèdica de Bellvitge-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Santiago
authors.initials: S
authors.lastname: Rello-Varona
authors.affiliation: Sarcoma Research Group, Institut d'Investigació Biomèdica de Bellvitge-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Herrero-Martín
authors.affiliation: Sarcoma Research Group, Institut d'Investigació Biomèdica de Bellvitge-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Oscar M
authors.initials: OM
authors.lastname: Tirado
mesh_terms: D000818:Animals; D051242:Caveolin 1 / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D020868:Gene Silencing; D006801:Humans; D020935:MAP Kinase Signaling System; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D015514:Oncogene Proteins, Fusion / Q000378:metabolism; D010766:Phosphorylation; D051789:Proto-Oncogene Protein c-fli-1 / Q000378:metabolism; D034802:RNA-Binding Protein EWS / Q000378:metabolism; D038601:Ribosomal Protein S6 / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism; D012512:Sarcoma, Ewing / Q000378:metabolism* / Q000473:pathology*; D020703:ras GTPase-Activating Proteins / Q000378:metabolism
chemical_list: C495540:CAV1 protein, human; D051242:Caveolin 1; C106031:EWS-FLI fusion protein; C101203:IQ motif containing GTPase activating protein 1; D015514:Oncogene Proteins, Fusion; D051789:Proto-Oncogene Protein c-fli-1; D034802:RNA-Binding Protein EWS; D038601:Ribosomal Protein S6; D020703:ras GTPase-Activating Proteins; C069329:RPS6KA1 protein, human; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
keywords: Ewing sarcoma; caveolin-1; mapk; metastasis; mmp9