Abstract 1421: Down-regulation of neuronal repressor gene REST inhibits tumor growth in Ewing's sarcoma

Abstract

Abstract Ewing's sarcoma is a peripheral primitive neuroectodermal tumors (PNET). The abnormal differentiation of neuronal stem cells may relate to tumorigenesis of Ewing's sarcoma. The RE1-silencing transcription factor (REST) is a neuronal repressor gene which regulates neuronal stem cell differentiation. The aim of this study is to investigate the role of REST in Ewing's sarcoma. Our results demonstrated that three human Ewing's sarcoma cell lines TC71, A4573 and SK-ES expressed high levels of REST. Six of seven tumor samples from patients with Ewing's sarcoma were shown REST positive. Transfection of EWS-FLI-1 into mesenchymal stem cells up-regulated REST expression. Down-regulation of EWS-FLI-1 using si-RNA inhibited REST expression in TC71 cells, suggesting EWS-FLI-1 fusion protein regulates REST expression in Ewing's sarcoma. The siRNA-REST stable transfected cell line was established to down-regulate REST expression in TC71 Ewing's sarcoma cells. In vivo experiments indicated that Ewing's sarcoma tumor growth was significantly inhibited in the mice injected with si-REST-TC71 cells compared to the mice injected with si-control cells. Down-regulation of REST inhibited cell proliferation and induced apoptosis in TC71 tumors. The immunohistochemical staining indicated that the tumor vessels and pericyte marker expression were reduced in si-REST tumor tissues. Inhibition of REST decreased the early neural differentiation marker MSX-1 expression and up-regulated the terminal neural differentiation marker β-Tubulin III (Tuj) expression. These data suggesting that neuronal repressor gene REST plays an important role in tumor development of Ewing's sarcoma. Inhibition of REST suppressed tumor growth and altered neuronal differentiation marker expression in Ewing's sarcoma. REST is a potential target for treatment of Ewing's sarcoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1421. doi:1538-7445.AM2012-1421