A Functional Polymorphism Rs2257440 In The Gene Dcr3 Regulates Its Expression Via Mtf-1 In Esophageal Squamous Cell Carcinoma

Purpose: The single nucleotide polymorphism (SNP) rs2257440 in exon 1 of the gene DcR3 is known to be significantly associated with susceptibility to esophageal squamous cell carcinoma (ESCC). In the present study, bioinformatics analysis indicated that the SNP might influence the binding of a transcription factor, metal regulatory transcription factor 1 (MTF-1), to its target gene. We further investigated whether the polymorphism rs2257440 could regulate DcR3 expression as a functional SNP via MTF-1. Methods and Results: Luciferase reporter assay indicated that MTF-1 elevated the expression of luciferase in the presence of the T allele of rs2257440 while no change in the expression was associated with the C allele of the polymorphism. Chromatin immunoprecipitation further evaluated the binding between the locus harboring the T allele and MTF-1. In the case of the TC genotype, over-expression of MTF-1 elevated DcR3 expression, which in turn promoted the invasion capacity of KYSE450 cells. However, there was no significant change in the invasion capacity of EC109 cells, which had the CC genotype. In the cancer cells of the ESCC patients, the expression of DcR3 was higher in the case of the TC or TT genotypes in comparison to the gene expression associated with the CC genotype. Over-expression of MTF-1 also decreased apoptosis of EC109 and KYSE450 cells, but the decrement was more in KYSE450 cells than in EC109 cells. Conclusions: Our finding indicates that rs2257440 is a functional SNP. The T allele of rs2257440 can increase DcR3 expression as it promotes binding of the gene with the specific transcription factor MTF-1. Therefore, the T allele of this polymorphism can decrease apoptosis and promote the invasion capacity of the cells in ESCC.