1. Caveolin-1 promotes Ewing sarcoma metastasis regulating MMP-9 expression through MAPK/ERK pathway
- Author
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Roser López-Alemany, Oscar M. Tirado, Juan Huertas-Martinez, Silvia Garcia-Monclús, Carlos Rodriguez-Galindo, Olga Almacellas-Rabaiget, Santiago Rello-Varona, Miguel Sáinz-Jaspeado, David Herrero-Martin, Laura Lagares-Tena, and Silvia Mateo-Lozano
- Subjects
0301 basic medicine ,MAPK/ERK pathway ,Pathology ,Oncogene Proteins, Fusion ,Caveolin 1 ,Metastasis ,Mice ,0302 clinical medicine ,IQGAP1 ,Cell Movement ,Medicine ,Neoplasm Metastasis ,Phosphorylation ,Mice, Inbred BALB C ,Ribosomal Protein S6 ,Kinase ,Soft tissue sarcoma ,Extracellular Matrix ,Matrix Metalloproteinase 9 ,Oncology ,ras GTPase-Activating Proteins ,030220 oncology & carcinogenesis ,FLI1 ,Female ,Sarcoma ,Research Paper ,caveolin-1 ,medicine.medical_specialty ,MAP Kinase Signaling System ,Mice, Nude ,Sarcoma, Ewing ,Ribosomal Protein S6 Kinases, 90-kDa ,03 medical and health sciences ,Cell Line, Tumor ,Animals ,Humans ,metastasis ,Neoplasm Invasiveness ,Gene Silencing ,mapk ,Proto-Oncogene Protein c-fli-1 ,business.industry ,medicine.disease ,030104 developmental biology ,mmp9 ,Cancer research ,RNA-Binding Protein EWS ,business ,Ewing sarcoma - Abstract
// Laura Lagares-Tena 1 , Silvia Garcia-Monclus 1 , Roser Lopez-Alemany 1 , Olga Almacellas-Rabaiget 1 , Juan Huertas-Martinez 1 , Miguel Sainz-Jaspeado 1 , Silvia Mateo-Lozano 2 , Carlos Rodriguez-Galindo 3 , Santiago Rello-Varona 1 , David Herrero-Martin 1 , Oscar M. Tirado 1 1 Sarcoma Research Group, Institut d’Investigacio Biomedica de Bellvitge-IDIBELL, L’Hospitalet de Llobregat, Barcelona, Spain 2 Developmental Tumor Biology Laboratory, Hospital Sant Joan de Deu, Barcelona, Spain 3 Pediatric Hematology/Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, Massachusetts, USA Correspondence to: Oscar M. Tirado, email: omartinez@idibell.cat Keywords: caveolin-1, Ewing sarcoma, metastasis, mmp9, mapk Received: December 22, 2015 Accepted: July 18, 2016 Published: July 28, 2016 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.
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- 2016