| Abstract: |
The presence of common genomic deletions in the 19q13 chromosomal region in neuroblastomas and gliomas strongly suggests the presence of a putative tumor suppressor gene for these neoplasms in this region that, despite much effort, has not yet been identified. In an attempt to address this issue, we compared the expression profile of 89 neuroblastoma tumors with that of benign ganglioneuromas by microarray analysis. Probe sets (637 of 62,839) were significantly down-regulated in neuroblastoma tumors, including, most importantly, a gene located at 19q13.3: the epithelial membrane protein 3 (EMP3), a myelin-related gene involved in cell proliferation and cell-cell interactions. We found that EMP3 undergoes hypermethylation-mediated transcriptional silencing in neuroblastoma and glioma cancer cell lines, whereas the use of the demethylating agent 5-aza-2-deoxycytidine restores EMP3 gene expression. Furthermore, the reintroduction of EMP3 into neuroblastoma cell lines displaying methylation-dependent silencing of EMP3 induces tumor suppressor-like features, such as reduced colony formation density and tumor growth in nude mouse xenograft models. Screening a large collection of human primary neuroblastomas (n = 116) and gliomas (n = 41), we observed that EMP3 CpG island hypermethylation was present in 24% and 39% of these tumor types, respectively. Furthermore, the detection of EMP3 hypermethylation in neuroblastoma could be clinically relevant because it was associated with poor survival after the first 2 years of onset of the disease (Kaplan-Meier; P = 0.03) and death of disease (Kendall τ, P = 0.03; r = 0.19). Thus, EMP3 is a good candidate for being the long-sought tumor suppressor gene located at 19q13 in gliomas and neuroblastomas. ©2005 American Association for Cancer Research. |
| Keywords: |
cancer survival; controlled study; human tissue; unclassified drug; human cell; methylation; nonhuman; glioma; brain neoplasms; neoplasm staging; cell proliferation; animal cell; mouse; animals; mice; gene expression profiling; animal model; down-regulation; genetic transcription; tumor xenograft; dna methylation; tumor suppressor gene; gene expression regulation, neoplastic; mice, nude; neuroblastoma; membrane glycoproteins; oligonucleotide array sequence analysis; epigenetics; cpg island; cpg islands; medulloblastoma; chromosomes, human, pair 19; 5 aza 2' deoxycytidine; down regulation; dna microarray; gene silencing; kaplan meier method; tumor growth; density; tumor suppressor protein; cell interaction; ganglioneuroma; molecular probe; genes, tumor suppressor; gene location; colony formation; chromosome 19q; epithelial membrane protein 3; myelin associated glycoprotein
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