Girnita L, Girnita A, Wang M, Meis-Kindblom J M, Kindblom L G, Larsson O
Department of Oncology and Pathology, Cellular and Molecular Tumor Pathology, CCK, R8:04, Karolinska Hospital, SE-171 76 Stockholm, Sweden.
Oncogene. 2000 Aug 31;19(37):4298-301. doi: 10.1038/sj.onc.1203755.
The EWS/FLI-1 fusion gene is characteristic of most cases of Ewing's sarcoma and has been shown to be crucial for tumor transformation and cell growth. In this study we demonstrate a drastic down-regulation of the EWS/FLI-1 protein, and a growth arrest, following serum depletion of Ewing's sarcoma cells. This indicates that growth factor circuits may be involved in regulation of the fusion gene product. Of four different growth factors tested, basic fibroblast growth factor (bFGF) was found to be of particular significance. In fact, upon treatment of serum-depleted cells with bFGF, expression of the EWS/FLI-1 protein and growth of the Ewing's sarcoma cells were restored. In addition, a bFGF-neutralizing antibody, which was confirmed to inhibit FGF receptor (FGFR) phosphorylation, caused down-regulation of EWS/FLI-1. Experiments using specific cell cycle blockers (thymidine and colcemide) suggest that EWS/FLI-1 is directly linked to bFGF stimulation, and not indirectly to cell proliferation. We also demonstrated expression of FGFRs in several tumor samples of Ewing's sarcoma. Taken together, our data suggest that expression of FGFR is a common feature of Ewing's sarcoma and, in particular, that the bFGF pathway may be important for the maintenance of a malignant phenotype of Ewing's sarcoma cells through up-regulating the EWS/FLI-1 protein. Oncogene (2000) 19, 4298 - 4301
EWS/FLI-1融合基因是大多数尤因肉瘤病例的特征，并且已被证明对肿瘤转化和细胞生长至关重要。在本研究中，我们证明了尤因肉瘤细胞血清饥饿后EWS/FLI-1蛋白的急剧下调以及生长停滞。这表明生长因子回路可能参与融合基因产物的调节。在测试的四种不同生长因子中，碱性成纤维细胞生长因子（bFGF）被发现具有特别重要的意义。事实上，用bFGF处理血清饥饿的细胞后，EWS/FLI-1蛋白的表达和尤因肉瘤细胞的生长得以恢复。此外，一种被证实可抑制成纤维细胞生长因子受体（FGFR）磷酸化的bFGF中和抗体导致EWS/FLI-1下调。使用特定细胞周期阻滞剂（胸腺嘧啶核苷和秋水仙酰胺）的实验表明，EWS/FLI-1与bFGF刺激直接相关，而不是与细胞增殖间接相关。我们还在尤因肉瘤的几个肿瘤样本中证明了FGFR的表达。综上所述，我们的数据表明FGFR的表达是尤因肉瘤的一个共同特征，特别是bFGF途径可能通过上调EWS/FLI-1蛋白对维持尤因肉瘤细胞的恶性表型很重要。《癌基因》（2000年）第19卷，4298 - 4301页
