19q13.33

Neuroblastoma / phaeochromocytoma

By methylation-specific PCR (MS-PCR) and direct bisulphate DNA sequencing, EMP3 hypermethylation is common in both tumor tissue (24-68.4%) and neuroblastoma cell lines (33.3%). It occurs with concomitant downregulation of EMP3 protein expression in all clinical samples and in only 33.3% of neuroblastoma cell lines (Alaminos et al., 2005; Margetts et al., 2008). EMP3 hypermethylation is associated with poor survival at two-year follow-up and with an high mortality rate (Alaminos et al., 2005).
In contrast, it is a rare event in sporadic (7.1%) and adult VHL-associated (6.1%) phaeochromocytomas (Margetts et al., 2008).

Brain tumors / gliomas

By MS-PCR, EMP3 hypermethylation is an early epigenetic event in gliomagenesis. It is common in pure (63%) and mixed (70%) oligodendroglial tumors in comparison to astrocytic ones (18%). It prevails in grade II (71.4%) upon grade III (44.7%) gliomas, and in secondary (89%) upon primary GBMs (17%) (Alaminos et al., 2005; Li et al., 2007; Kunitz et al., 2007; Mellai et al., 2013). Not found in GBM cell lines (Ernst et al., 2009).
Aberrant hypermethylation correlates with reduced mRNA expression and lack of EMP3 protein expression. It is strongly associated with IDH1/IDH2 somatic mutations in astrocytic and oligodendroglial tumors and inversely correlated with EGFR gene amplification. In oligodendrogliomas, it is also associated with loss of the 19q13.3 locus and with total 1p/19q co-deletion (Tews et al., 2006; Mellai et al., 2013), with prognostic significance on patient overall survival (Kunitz et al., 2007; Mellai et al., 2013).
The EMP3 gene belongs to the glioma CpG island methylator phenotype (G-CIMP) (Noushmehr et al., 2010), that identifies a distinct molecular glioma subclass, prevalent in low-grade tumors and associated with IDH1/2 mutations and with improved patient survival (Laffaire et al., 2011).
No tumor-specific mutations identified on 132 glioma patients, except for the SNPs rs4893 (p.Ile125Val, exon 5) and rs11671746 (3-UTR) in four patients (Kunitz et al., 2007).

Esophageal squamous cell carcinoma (ESCC)

By MS-PCR, EMP3 hpermethylation is rare in tumor tissue (6%) but frequent in ESCC cell lines (75%), with an inverse correlation with mRNA expression levels (Fumoto et al., 2009a). Low EMP3 expression is associated with poor prognosis after recurrence, suggesting that EMP3 inactivation may confer an advantage for tumor growth only at late stage of disease.

Breast cancer

By RT-PCR, EMP3 mRNA expression is significantly higher in primary tumors than in normal breast tissue. It correlates with the histologic grade III, lymph node metastatis and Her-2 expression in human mammary luminal epithelial cells (Mackey et al., 2003 ; Zhou et al., 2009). It may be a novel marker of tumor aggressiveness (Zhou et al., 2009).
By MS-PCR, EMP3 hypermethylation occurs occasionally in primary tumor tissue (36.5%) without association with mRNA expression levels. In breast cancer cell lines, EMP3 mRNA is frequently repressed in both invasive (70%) and non-invasive phenotype (75%). Promoter hypermethylation may explain mRNA repression in almost all the non-invasive phenotype and in only a part of the invasive phenotype (Evtimova et al., 2003).

Non-small cell lung cancer (NSCLC)

By Western blotting, EMP3 expression in tumor tissue is signifcantly lower than in normal lung tissue, correlates with the p-TNM stage and negatively with the proliferation index Ki-67. EMP3 may be a TSG at late stage of disease and a potential marker of prognosis in lung patients (Xue et al., 2013).
In lung cell lines, EMP3 is repressed with partial CpG hypermethylation in 11.1% of cases (Fumoto et al, 2009a).

Upper urinary tract urothelial carcinoma

At mRNA and protein level, EMP3 overexpression promotes in vitro tumor cell proliferation and migration by activation of the ErbB2-PI3K-AKT pathway. It suppresses cell adhesion. EMP3 and ErbB2 co-espression is the most important marker of progression-free and metastasis-free patient survival (Wang et al., 2013).

Prostate cancer

By a case-control study in 275 multiplex sibships on candidate genes and genomic regions with linkage to tumor suscpetibility and/or aggressiveness, the rs4893 variant displays a highly significant association, confirmed in a age-matched subsample. The EMP3 association, together with HPN: gene (19q11-q13.2), suggests the involvement of multiple genes within this genomic region in the prostate cancer susceptibility. The rs4893 allelic variant is significantly more frequent in prostate cancer patients compared to controls (Burmester et al., 2004).

Other malignancies

By RT-PCR, EMP3 displays high mRNA expression in gastric and colon cancer-derived cell lines (Fumoto et al., 2009b).

Keratoconus (KC)

By RT-PCR, EMP3 is significantly upregulated (2.5-fold) in keratoconus patients compared to a reference control group (Nielsen et al., 2005). EMP3 may have a potential role in the epithelial changes of the disease in agreement with the finding of blebs on the surface of KC corneas (Pfister and Burstein, 1977).