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Alaminos M, Davalos V, Ropero S, Setien F, Paz MF, Herranz M et al.. EMP3, a myelin-related gene located in the critical 19q13.3 region, is epigenetically silenced and exhibits features of a candidate tumor suppressor in glioma and neuroblastoma. Cancer Res 65: 2565-2571

Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, New York, United States
Cancer Research (Impact Factor: 9.28). 05/2005; 65(7):2565-71. DOI: 10.1158/0008-5472.CAN-04-4283
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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 tau, 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.

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    • "ethylation has not previously been reported in neuroblastoma or phaeochromocytoma . EMP3 is a peripheral myelin protein involved in cell proliferation and cell – cell interactions . Previously EMP3 expression was reported to be downregulated in glioma and neuroblastoma tumours , and EMP3 promoter methylation was detected in 24% of neuroblastomas ( Alaminos et al . 2005 ) . However , although we confirmed frequent EMP3 promoter methylation in neuroblastoma , EMP3 methylation did not appear to make a significant contribution to phaeochromocytoma tumourigenesis . Infrequent , or absent , promoter methylation was found for CTNNG ( g - catenin , also known as JUP ) and SYK in phaeochromocytoma . Although A"
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    • "Several genetic changes have been identifi ed in AAs and GBMs involving heterozygous deletion of 19q13, inactivation/deletion of tumor suppressor genes namely p16INK4A (Hegi et al. 1997), p14ARF (Ichimura et al. 2000), RB1 (Ichimura et al. 1996), PTEN and p53 gene (Mashiyama et al. 1991) and amplifi cation of EGFR gene (Libermann et al. 1985). Epigenetic research in glioma pathogenesis revealed several epigenetic genes silenced by promoter CpG island hypermethylation, such as, cell cycle regulatory proteins RB1 (Nakamura et al. 1996), p16INK4A (Costello et al. 1996; Fueyo et al. 1996), myelin related gene EMP3 (Alaminos et al. 2005), and matrix metalloproteinases inhibitor TIMP3 (Bachman et al. 1999). Comprehensive whole-genome microarray studies using inhibitors of epigenetic modifi cation have identified several genes including CST6 (putative metastatic suppressor), BIK (apoptosis inducer), TSPYL5 (unknown function), BEX1, and BEX2 (uncharacterized function) as putative tumor suppressors that are frequently methylated in primary gliomas (Kim et al. 2006; Foltz et al. 2006). "
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    • "More recently, the myelin-related epithelial membrane protein gene 3 (EMP3, 19q13.3) was found to be epigenetically silenced in malignant gliomas and neuroblastomas (Alaminos et al., 2005). We applied microarray-based expression profiling to identify novel genes that are differentially expressed between gliomas with and without 1p/19q losses (Tews et al., 2006). "
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