Functional role of S100A14 genetic variants and their association with esophageal squamous cell carcinoma.
S100 proteins have been implicated in various human diseases, including certain types of cancer. Among them, S100A14 is down-regulated in esophageal squamous cell carcinoma (ESCC). In this study, we sought to identify functional genetic variants in the S100A14 locus and assessed their associations with susceptibility to ESCC. Thirty individual DNA samples were sequenced to search for genetic variations in S100A14, and the function of the variants was investigated by a set of biochemical assays. A case-control analysis was performed in 1,021 patients with ESCC and 1,253 control subjects. Odds ratios and 95% confidence intervals (95% CI) were computed by logistic regression model. Four single nucleotide polymorphisms, -43A>G, 461G>A, 1493A>G, and 1545A>T, were identified in the S100A14 locus and they are in absolute linkage disequilibrium. Among them, the 461G>A change was shown to diminish a P53-binding site and is therefore associated with decreased expression of S100A14 in vitro and in vivo in the target tissues. Case-control analysis showed that the 461A allele was associated with susceptibility to ESCC among smokers, with the ORs being 2.01 (95% CI, 1.50-2.69) or 2.10 (95% CI, 1.37-3.22) for the 461GA or 461AA genotype, respectively, compared with the 461GG genotype. These data constitute strong evidence in support of the notion that S100A14 might function as a cancer suppressor working in the P53 pathway and play a role in esophageal carcinogenesis.
State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Hongyan
H
Chen
Dianke
D
Yu
Aiping
A
Luo
Wen
W
Tan
Chunpeng
C
Zhang
Dan
D
Zhao
Ming
M
Yang
Junniao
J
Liu
Dongxin
D
Lin
Zhihua
Z
Liu
D020121:5' Untranslated Regions; D002135:Calcium-Binding Proteins / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D016022:Case-Control Studies; D004938:Esophageal Neoplasms / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D015810:Linkage Disequilibrium; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D020121:5' Untranslated Regions; D002135:Calcium-Binding Proteins; C462950:S100A14 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53