EMP3 as a tumor suppressor gene for esophageal squamous cell carcinoma

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

doi:10.1016/j.canlet.2008.08.021

Cited by 31 publications

(29 citation statements)

References 26 publications

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“…Promoter hypermethylation and transcriptional silencing of the EMP3 gene was also observed in other cancers, like non‐small‐cell‐lung cancer and esophageal squamous carcinoma. Lower EMP3 expression levels were linked to shorter patient survival in both tumor entities . These observations seem to support a tumor suppressive role of EMP3.…”

Section: Introductionsupporting

confidence: 51%

Characterization of the epithelial membrane protein 3 interaction network reveals a potential functional link to mitogenic signal transduction regulation

Christians

Poisel

Hartmann

et al. 2019

Intl Journal of Cancer

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Epithelial Membrane Protein 3 (EMP3), a 4‐transmembrane glycoprotein, first gained attention as a putative tumor suppressor. Accumulating evidence, however, points to a more tumor promotive function of EMP3. The biological function of EMP3 remains largely unclear. To elucidate more of EMP3’s interaction network, we performed a Yeast‐Two‐Hybrid (Y2H) screening, followed by validation of candidate interactors by Biomolecular Fluorescence Complementation (BiFC) and Proximity Ligation Assay (PLA). Furthermore, we generated stable EMP3 knockdown cell lines and measured cell proliferation, migration and sensitivity to apoptosis induction as well as the expression and activation levels of important signal pathway components. The Y2H screening yielded 10 novel interactions of EMP3, eight of which could also be detected by BiFC and PLA interaction assays. All newly discovered interaction partners are involved in signaling or trafficking regulation. Most notably, FLOT1 and HTATIP2 have well described roles in the regulation of EGFR signaling. In addition, knockdown of EMP3 resulted in reduced levels of p‐AKT, p‐ERK and p‐EGFR, attenuated cell proliferation and migration and sensitized cells to apoptosis induction by TRAIL and Staurosporine. Based on these observations we hypothesize that EMP3 might be involved in the regulation of receptor‐tyrosine‐kinase mediated mitogenic signaling.

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Section: Introductionsupporting

confidence: 51%

Characterization of the epithelial membrane protein 3 interaction network reveals a potential functional link to mitogenic signal transduction regulation

Christians

Poisel

Hartmann

et al. 2019

Intl Journal of Cancer

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“…Furthermore, an inverse correlation between EMP3 promoter hypermethylation and mRNA expression levels has also been demonstrated in neuroblastoma, ESCC, and breast cancer cell lines [5, 11, 12]. In the present study, the correlation between EMP3 methylation status and transcript levels was not investigated.…”

Section: Discussionmentioning

confidence: 70%

Promoter Hypermethylation of theEMP3Gene in a Series of 229 Human Gliomas

Mellai

Piazzi

Caldera

et al. 2013

BioMed Research International

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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.

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“…Given the findings in the literature reporting a reduced expression level of EMP3 resulting from the methylation of its gene promoter (21,32), we thus assumed that in OII patients with LOH 19q, methylation of the gene copy located on the residual chromosome arm would imply its silencing, with an unfavorable outcome. Further support of this hypothesis is provided by the report of a more aggressive tumor phenotype associated with EMP3 promoter methylation in neuroblastoma patients (14), and by the finding that the re-expression of EMP3, induced by demethylating agents, is associated with lower tumorigenicity in neuroblastoma cell lines (demonstrated by lower in vitro colony formation and reduced tumor size of xenografts) (14).…”

Section: Genementioning

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 as a tumor suppressor gene for esophageal squamous cell carcinoma

Cited by 31 publications

References 26 publications

Characterization of the epithelial membrane protein 3 interaction network reveals a potential functional link to mitogenic signal transduction regulation

Characterization of the epithelial membrane protein 3 interaction network reveals a potential functional link to mitogenic signal transduction regulation

Promoter Hypermethylation of theEMP3Gene in a Series of 229 Human Gliomas

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

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