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: 9.33). 05/2005; 65(7):2565-71. DOI: 10.1158/0008-5472.CAN-04-4283
Source: PubMed


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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    • "Within tumors of the nervous system, DNA hypermethylation and aberrant expression of the EMP3 gene have been reported in both gliomas (24%) and neuroblastoma (39%) [5]. In the latter, the EMP3 hypermethylation may have a clinical relevance because it is associated with poor survival at two-year follow-up and with a higher mortality rate [5]. "
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    ABSTRACT: The epithelial membrane protein 3 (EMP3) is a candidate tumor suppressor gene in the critical region 19q13.3 for several solid tumors, including tumors of the nervous systems. The aim of this study was to investigate the EMP3 promoter hypermethylation status in a series of 229 astrocytic and oligodendroglial tumors and in 16 GBM cell lines. The analysis was performed by methylation-specific PCR and capillary electrophoresis. Furthermore, the EMP3 expression at protein level was evaluated by immunohistochemistry and Western blotting analysis. Associations of EMP3 hypermethylation with total 1p/19q codeletion, MGMT promoter hypermethylation, IDH1/IDH2 and TP53 mutations, and EGFR amplification were studied, as well as its prognostic significance. The EMP3 promoter hypermethylation has been found in 39.5% of gliomas. It prevailed in low-grade tumors, especially in gliomas with an oligodendroglial component, and in sGBMs upon pGBMs. In oligodendroglial tumors, it was strongly associated with both IDH1/IDH2 mutations and total 1p/19q codeletion and inversely with EGFR gene amplification. No association was found with MGMT hypermethylation and TP53 mutations. In the whole series, the EMP3 hypermethylation status correlated with 19q13.3 loss and lack of EMP3 expression at protein level. A favorable prognostic significance on overall survival of the EMP3 promoter hypermethylation was found in patients with oligodendroglial tumors.
    09/2013; 2013:756302. DOI:10.1155/2013/756302
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    • "Epithelial membrane protein 3 (EMP3) is a myelin-related gene associated with cell-cell interactions and cell proliferation. EMP3 promoter has been found hypermethylated and, so, silenced in primary gliomas and neuroblastoma, showing similar features than a tumor suppressor gene [26–29]. "
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    ABSTRACT: Gliomas are the most common type of primary brain tumor. Although tremendous progress has been achieved in the recent years in the diagnosis and treatment, its molecular etiology remains unknown. In this regard, epigenetics represents a new approach to study the mechanisms that control gene expression and function without changing the sequence of the genome. In the present paper we describe the main findings about the alterations of cell signaling pathways in the most aggressive glioma in the adult population, namely, glioblastoma, in which epigenetic mechanisms and the emerging role of cancer stem cell play a crucial function in the development of new biomarkers for its detection and prognosis and the corresponding development of new pharmacological strategies.
    07/2012; 2012:956958. DOI:10.1155/2012/956958
    • "In GBM, there is frequent hypermethylation of tumour suppressors (RB1, EMP3, RASSF1A and BLU), cell cycle regulators (p16INK4a and p15INK4b), DNA repair genes (MGMT, MLH1), and genes involved in tumour invasion and apoptosis (DAPK, TIMP3 and CDH1) (Alaminos et al., 2005; Costello et al., 1994; Fukushima et al., 2005; Gonzalez-Gomez et al., 2003; Herman et al., 1996; Hesson et al., 2004; Horiguchi et al., 2003; Nakamura et al., 2001b; Uhlmann et al., 2003). "
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    ABSTRACT: Cell type-specific patterns of gene expression reflect epigenetic changes imposed through a particular developmental lineage as well as those triggered by environmental cues within adult tissues. There is great interest in elucidating the molecular basis and functional importance of epigenetic mechanisms in both normal physiology and disease - particularly in cancer, where abnormal '-omic' states are often observed. In this article we review recent progress in studies of epigenetic mechanisms in the most common primary adult brain cancer, glioblastoma multiforme. Three distinct areas are discussed. First, the evidence in support of ongoing 'normal' epigenetic processes associated with differentiation - as predicted by 'cancer stem cell' models of the disease. Second, identification of site-specific and global epigenetic abnormalities. Third, genetic disruptions directly within the core epigenetic machinery, exemplified by the recently identified mutations within isocitrate dehydrogenase genes IDH1/2 and variant histone genes H3.3/H3F3A. These constitute the 'good, the bad and the ugly' of epigenetic mechanisms in cancer.
    Molecular Aspects of Medicine 07/2012; 34(4). DOI:10.1016/j.mam.2012.06.007 · 10.24 Impact Factor
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