Expression of esophageal cancer related gene 4 (ECRG4), a novel tumor suppressor gene, in esophageal cancer and its inhibitory effect on the tumor growth in vitro and in vivo

Abstract

The ECRG4 gene was initially identified and cloned in our laboratory from human normal esophageal epithelium (GenBank accession no. AF325503). We revealed the expression of ECRG4 protein was downregulated in 68.5% (89/130) ESCC samples using tissue microarray. The low ECRG4 protein expression was significantly associated with regional lymph node metastasis, primary tumor size, and tumor stage in ESCC (p < 0.05). ECRG4 mRNA expression was downregulated in ESCC due to the hypermethylation in the gene promoter. The treatment with 5-aza-2 0 -deoxycytidine, which is a DNA methyltransferase inhibitor restored ECRG4 mRNA expression in ESCC cells. The result indicated that promoter hypermethylation may be 1 main mechanism leading to the silencing of ECRG4. The high expression of ECRG4 in patients with ESCC was associated with longer survival compared with those with low ECRG4 expression by Kaplan-Meier survival analysis (p < 0.05). ECRG4 protein was an independent prognostic factor for ESCC by multivariable Cox proportional hazards regression analysis (p < 0.05). The restoration of ECRG4 expression in ESCC cells inhibited cell proliferation, colony formation, anchorage-independent growth, cell cycle progression and tumor growth in vivo (p < 0.05). The transfection of ECRG4 gene in ESCC cells inhibited the expression of NF-jB and nuclear translocation, in addition to the expression of COX-2, a NF-jB target gene, was attenuated. Taken together, ECRG4 is a novel candidate tumor suppressor gene in ESCC, and ECRG4 protein is a candidate prognostic marker for ESCC. ' 2009 UICC

Ecrg4 contributes to the anti-glioma immunosurveillance through type-I interferon signaling

“…[3][4][5][6] Moreover, several papers have shown the growth inhibitory effect of Ecrg4 when overexpressed in cancer cell lines. [7][8][9] Together, these findings suggested Ecrg4 as a tumor suppressor.…”

Soluble purified recombinant C2ORF40 protein inhibits tumor cell growth in vivo by decreasing telomerase activity in esophageal squamous cell carcinoma

“…In addition, C2ORF40 has been demonstrated to be chemosensitive to 5-fluorouracil and cisplatin (23,24). Previous research by the present authors demonstrated that C2ORF40 is a candidate tumor suppressor gene and an independent prognostic factor in ESCC, and C2ORF40 gene overexpression inhibits tumor cell proliferation and invasion in ESCC (25)(26)(27)(28)(29). Notably, additional bioinformatics analysis indicated that pro-C2ORF40 protein was a secreted protein with a signal peptide.…”

“…Among them p21 and p16 genes, critical cyclin-dependent kinase inhibitors, are hypothesized to be functionally relevant to the regulation of cell cycle G1 phase. Previous results have revealed that C2ORF40 transfection induces the upregulation of p21 expression in ESCC (25)(26)(27). However, there is no significant upregulation of p16 expression.…”

Growth Factors, Signal Transduction Pathways, and Tumor Suppressor Genes in Esophageal Cancer

“…ECRG4 is significantly associated with lymph node metastasis, tumor size, and tumor stage in SCCE, providing a candidate prognostic marker for SCCE [203].…”