...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Molecular Cancer >Loss of MEF2D expression inhibits differentiation and contributes to oncogenesis in rhabdomyosarcoma cells
【24h】

Loss of MEF2D expression inhibits differentiation and contributes to oncogenesis in rhabdomyosarcoma cells

机译：MEF2D表达的丧失抑制了横纹肌肉瘤细胞的分化并促进了肿瘤的发生

获取原文
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Background Rhabdomyosarcoma (RMS) is a highly malignant pediatric cancer that is the most common form of soft tissue tumors in children. RMS cells have many features of skeletal muscle cells, yet do not differentiate. Thus, our studies have focused on the defects present in these cells that block myogenesis. Methods Protein and RNA analysis identified the loss of MEF2D in RMS cells. MEF2D was expressed in RD and RH30 cells by transient transfection and selection of stable cell lines, respectively, to demonstrate the rescue of muscle differentiation observed. A combination of techniques such as proliferation assays, scratch assays and soft agar assays were used with RH30 cells expressing MEF2D to demonstrate the loss of oncogenic growth in vitro and xenograft assays were used to confirm the loss of tumor growth in vivo . Results Here, we show that one member of the MEF2 family of proteins required for normal myogenesis, MEF2D, is largely absent in RMS cell lines representing both major subtypes of RMS as well as primary cells derived from an embryonal RMS model. We show that the down regulation of MEF2D is a major cause for the failure of RMS cells to differentiate. We find that MyoD and myogenin are bound with their dimerization partner, the E proteins, to the promoters of muscle specific genes in RMS cells. However, we cannot detect MEF2D binding at any promoter tested. We find that exogenous MEF2D expression can activate muscle specific luciferase constructs, up regulate p21 expression and increase muscle specific gene expression including the expression of myosin heavy chain, a marker for skeletal muscle differentiation. Restoring expression of MEF2D also inhibits proliferation, cell motility and anchorage independent growth in vitro . We have confirmed the inhibition of tumorigenicity by MEF2D in a tumor xenograft model, with a complete regression of tumor growth. Conclusions Our data indicate that the oncogenic properties of RMS cells can be partially attributed to the loss of MEF2D expression and that restoration of MEF2D may represent a useful therapeutic strategy to decrease tumorigenicity.
机译：背景横纹肌肉瘤（RMS）是一种高度恶性的儿科癌症，是儿童软组织肿瘤的最常见形式。 RMS细胞具有骨骼肌细胞的许多特征，但没有分化。因此，我们的研究集中在这些细胞中阻碍肌发生的缺陷上。方法蛋白质和RNA分析鉴定了RMS细胞中MEF2D的丢失。通过瞬时转染和选择稳定细胞系分别在RD和RH30细胞中表达MEF2D，以证明观察到的肌肉分化得以挽救。诸如增殖测定，刮擦测定和软琼脂测定等技术与表达MEF2D的RH30细胞结合使用以证明体外致癌生长的损失，异种移植测定用于确认体内肿瘤生长的损失。结果在这里，我们显示正常肌发生所需的MEF2蛋白家族成员之一，即MEF2D，在代表RMS主要亚型的RMS细胞系以及衍生自胚胎RMS模型的原代细胞中均不存在。我们表明，MEF2D的下调是RMS细胞未能分化的主要原因。我们发现，MyoD和肌生成素与它们的二聚体伴侣E蛋白结合到RMS细胞中肌肉特异性基因的启动子上。但是，我们无法检测到任何启动子上的MEF2D结合。我们发现，外源性MEF2D表达可以激活肌肉特异性荧光素酶构建体，上调p21表达并增加肌肉特异性基因表达，包括肌球蛋白重链（骨骼肌分化的标志物）的表达。恢复MEF2D的表达在体外也抑制增殖，细胞运动和锚定独立生长。我们已经证实在异种移植肿瘤模型中，MEF2D抑制了致癌性，并完全消退了肿瘤的生长。结论我们的数据表明RMS细胞的致癌特性可部分归因于MEF2D表达的丧失，而MEF2D的恢复可能代表了降低致瘤性的有用治疗策略。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号