Caveolin-1 is down-regulated in alveolar rhabdomyosarcomas and negatively regulates tumor growth

// Juan Huertas-Martínez 1 , Santiago Rello-Varona 1 , David Herrero-Martín 1 , Ignasi Barrau 1 , Silvia García-Monclús 1 , Miguel Sáinz-Jaspeado 1 , Laura Lagares-Tena 1 , Yaiza Núñez-Álvarez 5 , Silvia Mateo-Lozano 2 , Jaume Mora 2 , Josep Roma 3 , Nuria Toran 3 , Sebastian Moran 4 , Roser López-Alemany 1 , Soledad Gallego 3 , Manel Esteller 4 , Miguel A. Peinado 5 , Xavier García del Muro 1 and Oscar M. Tirado 1 1 Sarcoma research group, Molecular Oncology Lab, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain 2 Developmental Tumor Biology Laboratory, Hospital Sant Joan de Deu, Barcelona, Spain 3 Biomedical Research Unit, Hospital Universitari Vall d'Hebron, Barcelona, Spain 4 Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L' Hospitalet de Llobregat, Barcelona, Spain 5 Institut de Medicina Predictiva i Personalitzada del Càncer, Badalona, Barcelona, Spain Correspondence: Oscar M. Tirado, email: // Keywords : alveolar rhabdomyosarcoma, Caveolin-1, muscular differentiation, 5-AZA-2'-deoxycytidine, epigenetics, cell death Received : June 26, 2014 Accepted : August 26, 2014 Published : August 27, 2014 Abstract Rhabdomyosarcoma is the most common soft tissue sarcoma of childhood and adolescence. Despite advances in therapy, patients with histological variant of rhabdomyosarcoma known as alveolar rhabdomyosarcoma (ARMS) have a 5-year survival of less than 30%. Caveolin-1 (CAV1), encoding the structural component of cellular caveolae, is a suggested tumor suppressor gene involved in cell signaling. In the present study we report that compared to other forms of rhabdomyosarcoma (RMS) CAV1 expression is either undetectable or very low in ARMS cell lines and tumor samples. DNA methylation analysis of the promoter region and azacytidine-induced re-expression suggest the involvement of epigenetic mechanisms in the silencing of CAV1. Reintroduction of CAV1 in three of these cell lines impairs their clonogenic capacity and promotes features of muscular differentiation. In vitro , CAV1-expressing cells show high expression of Caveolin-3 (CAV3), a muscular differentiation marker. Blockade of MAPK signaling is also observed. In vivo , CAV1-expressing xenografts show growth delay, features of muscular differentiation and increased cell death. In summary, our results suggest that CAV1 could function as a potent tumor suppressor in ARMS tumors. Inhibition of CAV1 function therefore, could contribute to aberrant cell proliferation, leading to ARMS development.