miR-34a functions as a tumor suppressor modulating EGFR in glioblastoma multiforme.
miR-34a functions as a tumor suppressor modulating EGFR in glioblastoma multiforme.
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miR-34a 在多形性胶质母细胞瘤中作为肿瘤抑制因子调节 EGFR
DOI：
10.1038/onc.2012.132
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发表时间：
2013-02-28
期刊：
影响因子：
8
通讯作者：
Koeffler, H. Phillip
中科院分区：
文献类型：
--
作者：
Yin, D.;Ogawa, S.;Kawamata, N.;Leiter, A.;Ham, M.;Li, D.;Doans, N. B.;Said, J. W.;Black, K. L.;Koeffler, H. Phillip
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 微阵列在 55 个 GBM 的基因组 DNA 中，miR-34a 经常被删除，表皮生长因子受体 (EGFR) 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 的表达显着降低。 GBM 细胞中 miR-34a 的强制表达降低了其迁移能力，并显着降低了细胞周期蛋白 A1、-B1、-D1 和 -D3 以及细胞周期蛋白依赖性激酶的水平，并增加了细胞周期蛋白激酶抑制剂蛋白的表达 (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更小的肿瘤。此外，强制过度表达 miR-34a 的细胞中 EGFR 蛋白表达降低。其他研究表明，mir-34a 靶向 Yin Yang-1 (YY1)，YY1 是一种转录因子，可以刺激 EGFR 的表达。因此，我们的数据表明，miR-34a 通过在体外和体内抑制 GBM 细胞的生长来充当肿瘤抑制剂，并与调节细胞周期蛋白和 EGFR 的表达相关。此外，我们首次发现 miR-34a 的缺失和 EGFR 的扩增均与 GBM 患者的总生存期显着降低相关。
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.
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通讯作者：
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