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

Juan Huertas-Martínez,Silvia Mateo-Lozano,Jaume Mora,Soledad Gallego,Manel Esteller,Miguel Sáinz-Jaspeado,Laura Lagares-Tena,Oscar M Tirado,Xavier García Del Muro,David Herrero-Martín,Sebastian Moran,Nuria Toran,Josep Roma,Santiago Rello-Varona,Silvia García-Monclús,Ignasi Barrau,Miguel A Peinado,Yaiza Núñez-Álvarez,Roser López-Alemany

doi:10.18632/oncotarget.2403

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.

Highlights

Rhabdomyosarcoma (RMS) is a rare soft tissue sarcoma, more frequent in children, accounting for 3-4% of childhood cancers
PAX3/7-FOXO1 aberrant fusion proteins behave as oncoproteins deregulating PAX3 and PAX7 transcription factor networks that play a role in skeletal muscle development, altering aspects of the muscle development, growth and/or maintenance
To further determine the expression levels of CAV1 in RMS cell lines and patients, we analyzed its expression by western blot in a panel of human cell lines and by immunohistochemistry (IHC) in a tissue microarray (TMA) of 70 patients (Figure 1 and Supplementary Table S1)

Summary

Introduction

Rhabdomyosarcoma (RMS) is a rare soft tissue sarcoma, more frequent in children, accounting for 3-4% of childhood cancers. RMS comprises two histological subtypes, alveolar (ARMS) and embryonal (ERMS), each of them with different prognosis and various genetic and molecular alterations. Www.impactjournals.com/oncotarget (q35;q14) or t(1;13)(p36;q14) in 70 to 85% of cases. These translocations give rise to the fusion of the PAX3 or PAX7 transcription factor to the forkhead (FOXO1) transcription factor. PAX3/7-FOXO1 aberrant fusion proteins behave as oncoproteins deregulating PAX3 and PAX7 transcription factor networks that play a role in skeletal muscle development, altering aspects of the muscle development, growth and/or maintenance. In the end PAX/FOXO1 proteins drive neoplastic transformation of skeletal muscle lineage cells towards malignant, developmentally arrested primitive myoblasts [5]

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Conclusion