title: miR-34a functions as a tumor suppressor modulating EGFR in glioblastoma multiforme.
abstract: 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.
authors.affiliation: Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes, Research Center of Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China. Dong.Yin@cshs.org
authors.forename: D
authors.initials: D
authors.lastname: Yin
authors.forename: S
authors.initials: S
authors.lastname: Ogawa
authors.forename: N
authors.initials: N
authors.lastname: Kawamata
authors.forename: A
authors.initials: A
authors.lastname: Leiter
authors.forename: M
authors.initials: M
authors.lastname: Ham
authors.forename: D
authors.initials: D
authors.lastname: Li
authors.forename: N B
authors.initials: NB
authors.lastname: Doan
authors.forename: J W
authors.initials: JW
authors.lastname: Said
authors.forename: K L
authors.initials: KL
authors.lastname: Black
authors.forename: H
authors.initials: H
authors.lastname: Phillip Koeffler
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D005784:Gene Amplification; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D005909:Glioblastoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000502:physiology*; D014183:Transplantation, Heterologous; D050986:YY1 Transcription Factor / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D050986:YY1 Transcription Factor; C494698:YY1 protein, human; D066246:ErbB Receptors