miR-34a functions as a tumor suppressor modulating EGFR in glioblastoma multiforme

• Published in: Oncogene Vol. 32; no. 9; pp. 1155 - 1163
• Main Authors: Yin, D, Ogawa, S, Kawamata, N, Leiter, A, Ham, M, Li, D, Doan, N B, Said, J W, Black, K L, Phillip Koeffler, H
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 28.02.2013; Nature Publishing Group
• Subjects: 631/208/199; 631/337/384/331; 631/67/1922; Animals; Apoptosis; Brain; Brain cancer; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Care and treatment; Cell Biology; Cell Cycle Proteins - metabolism; Cell Line, Tumor; Chromosome 1; Chromosomes; Comparative analysis; Cyclin-dependent kinase; Cyclin-dependent kinase inhibitor p27; Cyclin-dependent kinases; Deoxyribonucleic acid; DNA; DNA microarrays; Enzyme inhibitors; Epidermal growth factor; Epidermal growth factor receptors; Gene Amplification; Gene Deletion; Gene Expression Regulation, Neoplastic; Genes, Tumor Suppressor; Genetic aspects; Glioblastoma; Glioblastoma - genetics; Glioblastoma - mortality; Glioblastoma - pathology; Glioblastoma multiforme; Health aspects; Human Genetics; Humans; Immunodeficiency; Internal Medicine; Medicine; Medicine & Public Health; Mice; Mice, Nude; MicroRNAs - physiology; Oncology; original-article; Physiological aspects; Polymorphism; Receptor, Epidermal Growth Factor - genetics; Receptor, Epidermal Growth Factor - metabolism; Risk factors; Single-nucleotide polymorphism; Transplantation, Heterologous; Tumor suppressor genes; Tumors; Xenografts; YY1 protein; YY1 Transcription Factor - metabolism; United States; glioblastoma multiforme; genomic profiling; miR-34a; YY-1; EGFR
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2012.132

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.