期刊
ONCOGENE
卷 32, 期 9, 页码 1155-1163出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2012.132
关键词
glioblastoma multiforme; genomic profiling; miR-34a; EGFR; YY-1
资金
- National Institutes of Health [1U54CA143930-02, 5R01CA026038-32]
- Tom Collier Foundation
- A *STAR award of Singapore
- Maxine Dunitz Neurosurgical Institute
- Cedars-Sinai Medical Center
- NSFC [81071788]
- '985 project' of Sun Yat-sen University
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. Oncogene (2013) 32, 1155-1163; doi:10.1038/onc.2012.132; published online 14 May 2012
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