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
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"
ABSTRACT: The molecular genetics of inherited phaeochromocytoma have received considerable attention, but the somatic genetic and epigenetic events that characterise tumourigenesis in sporadic phaeochromocytomas are less well defined. Previously, we found considerable overlap between patterns of promoter region tumour suppressor gene (TSG) hypermethylation in two neural crest tumours, neuroblastoma and phaeochromocytoma. In order to identify candidate biomarkers and epigenetically inactivated TSGs in phaeochromocytoma and neuroblastoma, we characterised changes in gene expression in three neuroblastoma cell lines after treatment with the demethylating agent 5-azacytidine. Promoter region methylation status was then determined for 28 genes that demonstrated increased expression after demethylation. Three genes HSP47, homeobox A9 (HOXA9) and opioid binding protein (OPCML) were methylated in >10% of phaeochromocytomas (52, 17 and 12% respectively). Two of the genes, epithelial membrane protein 3 (EMP3) and HSP47, demonstrated significantly more frequent methylation in neuroblastoma than phaeochromocytoma. These findings extend epigenotype of phaeochromocytoma and identify candidate genes implicated in sporadic phaeochromocytoma tumourigenesis.Endocrine Related Cancer 05/2008; 15(3):777-86. DOI:10.1677/ERC-08-0072 · 4.91 Impact Factor
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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). "
ABSTRACT: Brain tumor is associated with poor prognosis. The treatment option is severely limited for a patient with brain tumor, despite great advances in understanding the etiology and molecular biology of brain tumors that have lead to breakthroughs in developing pharmaceutical strategies, and ongoing NCI/Pharma-sponsored clinical trials. We reviewed the literature on molecular targeted agents in preclinical and clinical studies in brain tumor for the past decade, and observed that the molecular targeting in brain tumors is complex. This is because no single gene or protein can be affected by single molecular agent, requiring the use of combination molecular therapy with cytotoxic agents. In this review, we briefly discuss the potential molecular targets, and the challenges of targeted brain tumor treatment. For example, glial tumors are associated with over-expression of calcium-dependent potassium (K(Ca)) channels, and high grade glioma express specific K(Ca) channel gene (gBK) splice variants, and mutant epidermal growth factor receptors (EGFRvIII). These specific genes are promising targets for molecular targeted treatment in brain tumors. In addition, drugs like Avastin and Gleevec target the molecular targets such as vascular endothelial cell growth factor receptor, platelet-derived growth factor receptors, and BRC-ABL/Akt. Recent discovery of non-coding RNA, specifically microRNAs could be used as potential targeted drugs. Finally, we discuss the role of anti-cancer drug delivery to brain tumors by breaching the blood-brain tumor barrier. This non-invasive strategy is particularly useful as novel molecules and humanized monoclonal antibodies that target receptor tyrosine kinase receptors are rapidly being developed.Drug Target Insights 08/2007; 2:197-207.
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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). "
ABSTRACT: Deletions of chromosomal arms 1p and 19q are frequent in oligodendroglial tumours and have been associated with sensitivity to radio- and chemotherapy as well as favourable prognosis. By using microarray-based expression profiling, we found that oligodendroglial tumours with 1p and 19q losses showed significantly lower expression of the CBP/p300-interacting transactivator with glutamic acid/aspartic acid-rich carboxyl-terminal domain 4 gene (CITED4) at 1p34.2 as compared to tumours without 1p and 19q losses. Mutational analysis showed no CITED4 mutations in gliomas. However, 1p and 19q losses as well as low expression of CITED4 transcripts were significantly associated with hypermethylation of the CITED4-associated CpG island. In line with the latter finding, treatment of CITED4 hypermethylated glioma cell lines with 5-aza-2'-deoxycytidine and trichostatine A resulted in a marked increase of the CITED4 transcript levels. Furthermore, CITED4 hypermethylation was significantly associated with longer recurrence-free and overall survival of patients with oligodendroglial tumours. Taken together, our results indicate that CITED4 is epigenetically silenced in the vast majority of oligodendroglial tumours with 1p and 19q deletions and suggest CITED4 hypermethylation as a novel prognostic marker in oligodendroglioma patients.Oncogene 08/2007; 26(34):5010-6. DOI:10.1038/sj.onc.1210297 · 8.56 Impact Factor