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首页> 外文期刊>Oncogene >MiR-34a functions as a tumor suppressor modulating EGFR in glioblastoma multiforme
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MiR-34a functions as a tumor suppressor modulating EGFR in glioblastoma multiforme

机译：MiR-34a 在多形性胶质母细胞瘤中作为调节 EGFR 的抑癌基因发挥作用

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摘要

Chromosome 1p36.23 is frequently deleted in glioblastoma multiforme (GBM). miR-34a localizes in this region. Our experiments found that miR-34a was often deleted and epidermal growth factor receptor (EGFR) was frequently amplified in genomic DNA of 55 GBMs using single-nucleotide polymorphism DNA microarray. Notably, we found that the mean survival time was significantly shortened for patients whose GBMs had both EGFR amplification and miR-34a deletion. Expression of miR-34a was significantly lower in GBM samples compared with normal brain tissue. Forced expression of miR-34a in GBM cells decreased their ability to migrate and profoundly decreased their levels of cyclin-A1, -B1, -D1, and -D3, as well as cyclin-dependent kinase and increased expression of cyclin kinase inhibitor proteins (p21, p27). Also, human GBM cells (U251) stable overexpressing mir-34a formed smaller tumors when growing as xenografts in immunodeficient mice compared with wild-type U251 GBM cells. Furthermore, the protein expression of EGFR decreased in the cells with forced overexpression of miR-34a. Additional studies showed that mir-34a targeted Yin Yang-1 (YY1) and YY1 is a transcription factor that can stimulate the expression of EGFR. Thus, our data suggest that miR-34a acts as a tumor suppressor by inhibiting growth of GBM cells in vitro and in vivo associated with moderating the expression of cell-cycle proteins and EGFR. Moreover, we discovered for the first time that both deletion of miR-34a and amplification of EGFR were associated with significantly decreased overall survival of GBM patients.
机译：染色体 1p36.23 在多形性胶质母细胞瘤 （GBM） 中经常被删除。miR-34a定位于该区域。我们的实验发现，使用单核苷酸多态性 DNA 微阵列，miR-34a 经常被缺失，表皮生长因子受体 （EGFR） 在 55 GBMs 的基因组 DNA 中经常被扩增。值得注意的是，我们发现GBM同时具有EGFR扩增和miR-34a缺失的患者的平均生存时间显着缩短。与正常脑组织相比，GBM 样本中 miR-34a 的表达显著降低。在GBM细胞中，miR-34a的强制表达降低了它们的迁移能力，并大大降低了细胞周期蛋白-A1、-B1、-D1和-D3的水平，以及细胞周期蛋白依赖性激酶和细胞周期蛋白激酶抑制蛋白的表达增加（p21，p27）。此外，与野生型 U251 GBM 细胞相比，稳定过表达 mir-34a 的人 GBM 细胞 （U251） 在免疫缺陷小鼠中作为异种移植物生长时形成较小的肿瘤。此外，随着miR-34a的强制过表达，EGFR蛋白在细胞中的表达降低。其他研究表明，mir-34a 靶向阴阳-1 （YY1），YY1 是一种可以刺激 EGFR 表达的转录因子。因此，我们的数据表明，miR-34a 通过抑制体外和体内 GBM 细胞的生长来充当肿瘤抑制因子，从而调节细胞周期蛋白和 EGFR 的表达。此外，我们首次发现miR-34a的缺失和EGFR的扩增都与GBM患者总生存期的显著降低有关。

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  • 来源
    《Oncogene》 |2013年第9期|1155-1163|共9页
  • 作者

    YinD.; OgawaS.; KawamataN.LeiterA.HamM.LiD.DoanN.B.SaidJ.W.BlackK.L.PhillipKoefflerH.;

  • 作者单位

    Key Laboratory of Malignant Tumor Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen;

    Regeneration Medicine of Hematopoiesis, School of Medicine, University of Tokyo, Tokyo, Japan;

    Division of Hematology and Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, 8700Los Angeles Biomedical Research Institute, Harbor UCLA Medical Center, 1124 West Carson StreetDepartment of Pathology, UCLA School of Medicine, Los Angeles, CA, United StatesMaxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, UCLA School of Medicine, Los;

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  • 原文格式 PDF
  • 正文语种 英语
  • 中图分类 肿瘤学;
  • 关键词

    EGFR; genomic profiling; glioblastoma multiforme; miR-34a; YY-1;

    机译：EGFR;基因组分析;多形性胶质母细胞瘤;miR-34a;YY-1型;

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