Potikyan Gary, Savene Rupert O V, Gaulden Julie M, France Kelly A, Zhou Zhichao, Kleinerman Eugenie S, Lessnick Stephen L, Denny Christopher T
Molecular Biology Institute, Jonsson Comprehensive Cancer Center, University of California-Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90024, USA.
Cancer Res. 2007 Jul 15;67(14):6675-84. doi: 10.1158/0008-5472.CAN-06-4140.
Suppression of the expression of antiangiogenic factors has been closely associated with multiple malignancies. Thrombospondins 1 and 2 are members of a family of angiogenic inhibitors that are regulated by several oncogenes. In this study, we investigate the role of thrombospondins in Ewing's sarcoma and their regulation by EWS/ETS fusion oncoproteins. We show that the EWS/FLI1 fusion suppresses the expression of thrombospondins in both NIH3T3 fibroblasts and Ewing's sarcoma tumor-derived cell lines. This regulation depends on an intact EWS/FLI1 DNA-binding domain and may involve direct interactions between EWS/FLI1 and thrombospondin promoter regions. Forced expression of thrombospondins in Ewing's sarcoma cell lines inhibited the rate of tumor formation in vivo and markedly decreased the number of microvessels present in the tumors. These findings suggest that thrombospondins play a biologically significant role in tumor vascularization in Ewing's sarcoma and suggest potential therapeutic strategies for future therapeutic intervention.
抗血管生成因子表达的抑制与多种恶性肿瘤密切相关。血小板反应蛋白1和2是一类血管生成抑制剂家族的成员，它们受多种癌基因调控。在本研究中，我们调查了血小板反应蛋白在尤因肉瘤中的作用及其受EWS/ETS融合癌蛋白的调控情况。我们发现EWS/FLI1融合蛋白在NIH3T3成纤维细胞和尤因肉瘤肿瘤衍生细胞系中均抑制血小板反应蛋白的表达。这种调控依赖于完整的EWS/FLI1 DNA结合结构域，可能涉及EWS/FLI1与血小板反应蛋白启动子区域之间的直接相互作用。在尤因肉瘤细胞系中强制表达血小板反应蛋白可抑制体内肿瘤形成率，并显著减少肿瘤中微血管的数量。这些发现表明血小板反应蛋白在尤因肉瘤的肿瘤血管生成中发挥着生物学上的重要作用，并为未来的治疗干预提供了潜在的治疗策略。
