<i>EMP3</i>as a candidate tumor suppressor gene for solid tumors

Fumoto, Shoichi; Tanimoto, Keiji; Hiyama, Eiso; Noguchi, Tsuyoshi; Nishiyama, Masahiko; Hiyama, Keiko

doi:10.1517/14728220902988549

Cited by 19 publications

(13 citation statements)

References 32 publications

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“…We observed that this three-gene (EMP3, GSX2 and EMILIN3 ) signature can be used as a prognostic indicator for LGGs patients from both the TCGA and the CGGA datasets. EMP3 is a member of the PMP22/EMP/MP20 gene family that plays a role in cell proliferation and cell-cell interactions [27]. Previous studies reported that CpG island hypermethylation in the EMP3 promoter region is frequent in LGGs [28-30].…”

Section: Discussionmentioning

confidence: 99%

Integrative Analysis of DNA Methylation and Gene Expression Identify a Three-Gene Signature for Predicting Prognosis in Lower-Grade Gliomas

Zeng

Liu

et al. 2018

Cell Physiol Biochem

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Background/Aims: In the current study, we performed an integrated analysis of genome-wide methylation and gene expression data to find novel prognostic genes for lower-grade gliomas (LGGs). Methods: First, TCGA methylation data were used to identify prognostic genes associated with promoter methylation. Second, candidate genes that were stably regulated by promoter methylation were explored. Third, Cox proportional hazards regression analysis was used to generate a prognostic signature, and the signature genes were used to construct a survival risk score system. Results: Three genes (EMP3, GSX2 and EMILIN3) were selected as signature genes. These three signature genes were used to construct a survival risk score system. The high-risk group exhibited significantly worse overall survival (OS) and relapse-free survival (RFS) as compared to the low-risk group in the TCGA dataset. The association of the three-gene prognostic signature with patient’ survival was then validated using the CGGA dataset. Moreover, Kaplan-Meier plots showed that the three-gene prognostic signature risk remarkably stratified grade II and grade III patients in terms of both OS and RFS in the TCGA cohort. There was also a significant difference between the low- and high-risk groups in IDH wild-type glioma patients, indicating that the three-gene signature may be able to help in predicting prognosis for patients with IDH wild-type gliomas. Conclusion: We identified and validated a three-gene (EMP3, GSX2 and EMILIN3) prognostic signature in LGGs by integrating multidimensional genomic data from the TCGA and CGGA datasets, which may help in fine-tuning the current histology-based tumors classification system and providing better stratification for future clinical trials.

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Section: Discussionmentioning

confidence: 99%

Integrative Analysis of DNA Methylation and Gene Expression Identify a Three-Gene Signature for Predicting Prognosis in Lower-Grade Gliomas

Zeng

Liu

et al. 2018

Cell Physiol Biochem

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“…In our previous study (22), we identified a subgroup of patients with a shorter disease-free interval and LOH 19q, a cytogenetic alteration frequently observed in OII (27,28) but not in GBM (29). We thus decided to evaluate in the same patients the methylation status of the EMP3 gene promoter located in the 19q chromosome region (19q13.3), which has gained increasing interest as it is considered a candidate tumor suppressor gene for solid tumors (15), including brain tumors. The hypermethylated status of the EMP3 gene promoter in low-grade gliomas is known as a molecular feature distinguishing them from highgrade gliomas (20,21).…”

Section: Discussionmentioning

confidence: 99%

“…The epigenetic profiling of brain tumors has indeed significance as a prognostic index (10): e.g., the epigenetic silencing of O 6 -methylguanine methyltransferase (MGMT, 10q26) correlates with responsiveness to alkylating agents and radiotherapy in glioblastoma (GBM, WHO grade IV) (11)(12)(13). The 19q region, frequently lost in ODG tumors, harbors putative tumor suppressor genes, such as the epithelial membrane protein 3 (EMP3, 19q13.3) (14)(15)(16)(17)(18)(19). The function of EMP3 remains unclear; however, its homology to peripheral myelin protein 22 (PMP22) suggests that the protein is implicated in cell cycle regulation and cell-to-cell interactions (17).…”

Section: Introductionmentioning

confidence: 99%

LOH 19q indicates shorter disease progression-free interval in low-grade oligodendrogliomas with EMP3 methylation

et al. 2012

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Abstract. We previously described a cohort of grade II oligodendroglioma (OII) patients, in whom the loss of heterozygosity (LOH) 19q was present in the subgroup at a higher risk of relapse. In this study, we evaluated the CpG methylation of the putative tumor suppressor epithelial membrane protein 3 (EMP3, 19q13.3) gene promoter in the same OII cohort, to investigate whether a correlation could be found between EMP3 cytogenetic and epigenetic loss and higher risk of relapse. Twenty-three tumor samples from OII patients were collected over a period of 10 years. Seventeen glioblastoma (GBM) samples (2 of which were relapses) were collected from 15 patients. The EMP3, O 6 -methylguanine methyltransferase (MGMT) and cyclooxygenase 2 (COX2) promoter methylation, evaluated by methylation-specific PCR, and the isocitrate dehydrogenase 1 (IDH1) mutation, identified by sequencing, were compared between the OII and GBM histotypes. The EMP3 promoter methylation was correlated with the analysis of LOH 19q, performed by microsatellite amplification, in OII patients. Disease progression-free interval was evaluated in the OII patients with the EMP3 methylation with either LOH 19q or conserved chromosome 19 arms. The EMP3 and MGMT promoter methylation was more frequent in OII than in GBM patients, and the IDH1 mutation was absent in GBM. The COX2 promoter was unmethylated in both histotypes. Both LOH +/-19q OII patients showed EMP3 hypermethylation. Concomitant LOH 19q and EMP3 gene promoter methylation was observed in the OII patients at a higher risk of relapse. Our results suggest that a total (cytogenetic and epigenetic) functional loss of both EMP3 alleles accounts for the reduced disease progression-free interval in OII patients. Although the small sample size limits the strength of this study, our results support testing this hypothesis in larger cohorts of patients, considering the methylation of the EMP3 gene promoter together with LOH 19q as an indication for treatment with adjuvant therapy ab initio in order to improve the overall survival of OII patients.

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“…EMP3 is expressed in most tissues, especially in peripheral blood leukocytes, ovary, intestine, and various embryonic tissues, and may regulate cell proliferation, cell-cell interactions, and apoptosis [2–4]. The EMP3 gene has been proposed as a candidate tumor suppressor gene on 19q13.3 in several human solid tumors, such as gliomas, neuroblastoma, pheochromocytoma, non-small cell lung cancer, and esophageal squamous cell carcinoma [5–9]. In these malignancies, EMP3 is frequently inactivated by a hypermethylation-mediated transcriptional gene silencing.…”

Section: Introductionmentioning

confidence: 99%

Epithelial membrane protein 3 regulates TGF-β signaling activation in CD44-high glioblastoma

Hong

Liu

et al. 2016

Oncotarget

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Although epithelial membrane protein 3 (EMP3) has been implicated as a candidate tumor suppressor gene for low grade glioma, its biological function in glioblastoma multiforme (GBM) still remains poorly understood. Herein, we showed that EMP3 was highly expressed in CD44-high primary GBMs. Depletion of EMP3 expression suppressed cell proliferation, impaired in vitro tumorigenic potential and induced apoptosis in CD44-high GBM cell lines. We also identified TGF-β/Smad2/3 signaling pathway as a potential target of EMP3. EMP3 interacts with TGF-βreceptor type 2 (TGFBR2) upon TGF-βstimulation in GBM cells. Consequently, the EMP3-TGFBR2 interaction regulates TGF-β/Smad2/3 signaling activation and positively impacts on TGF-βstimulated gene expression and cell proliferation in vitro and in vivo. Highly correlated protein expression of EMP3 and TGF-β/Smad2/3 signaling pathway components was also observed in GBM specimens, confirming the clinical relevancy of activated EMP3/TGF-β/Smad2/3 signaling in GBM. In conclusion, our findings revealed that EMP3 might be a potential target for CD44-high GBMs and highlight the essential functions of EMP3 in TGF-β/Smad2/3 signaling activation and tumor progression.

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EMP3as a candidate tumor suppressor gene for solid tumors

Abstract: EMP3 is a novel tumor suppressor gene in some kinds of malignancies, but not all, at the step of cellular immortalization rather than carcinogenesis. It may become a potent prognostic marker and a therapeutic target in such tumors.

Cited by 19 publications

References 32 publications

Integrative Analysis of DNA Methylation and Gene Expression Identify a Three-Gene Signature for Predicting Prognosis in Lower-Grade Gliomas

Integrative Analysis of DNA Methylation and Gene Expression Identify a Three-Gene Signature for Predicting Prognosis in Lower-Grade Gliomas

LOH 19q indicates shorter disease progression-free interval in low-grade oligodendrogliomas with EMP3 methylation

Epithelial membrane protein 3 regulates TGF-β signaling activation in CD44-high glioblastoma

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