Abstract
MDM4 is a p53-interacting protein and plays an important role in carcinogenesis. In this study of 1,077 gastric cancer (GCa) cases and 1,173 matched cancer-free controls, we investigated associations between three tagging single nucleotide polymorphisms (SNPs) (rs11801299 G>A, rs1380576 C>G and rs10900598 G>T) in MDM4 and gastric cancer risk in an Eastern Chinese Population. In logistic regression analysis, a significantly decreased GCa risk was associated with the rs1380576 GG variant genotype (adjusted odds ratio [OR] =0.74, 95% confidence interval [CI] =0.56-0.98) under a recessive model, which remained significant after correction by the false-positive reporting probability. This risk was more evident in subgroups of older subjects, males, never smokers, never drinkers and cancers of non-cardia. We then performed SNP-mRNA expression correlation analysis and found that the GG variant genotype was associated with significantly decreased expression of MDM4 mRNA in normal cell lines for 44 Chinese (P=0.032 for GG vs. CC) as well as for 269 multi-ethnic subjects (P<0.0001 for GG vs. CC). Our results suggest that the MDM4 rs1380576 G variant may be markers for GCa susceptibility. Larger, independent studies are warranted to validate our findings.
Highlights
Gastric cancer was the fourth most common cancer worldwide and is the second most common cause of death from cancer, with an estimated 951,600 new cases and 723,100 deaths in 2012 [1]
A significantly decreased gastric cancer (GCa) risk was associated with the rs1380576 GG variant genotype under a recessive model, which remained significant after correction by the false-positive reporting probability
The etiology of gastric cancer is still unclear, multiple factors are thought to play a role in gastric carcinogenesis, including Helicobacter pylori (H. pylori) infection [2], nutrition deficiency, high intake of various traditional salt-preserved foods or salt and chemical carcinogenesis existing in tobacco [3, 4]
Summary
Gastric cancer was the fourth most common cancer worldwide and is the second most common cause of death from cancer, with an estimated 951,600 new cases and 723,100 deaths in 2012 [1]. The p53 pathway has been shown to be crucial in preventing tumor formation, and the disruption of p53 function commonly leads to the initiation or progression of tumors [5]. The murine double minute protein MDM2 is an established regulator of p53, which can directly bind to p53 protein, inhibit its activity and lead to its degradation www.impactjournals.com/oncotarget via the ubiquitination pathway [6]. As a structural homolog of MDM2, MDM4 has recently emerged as another p53-interacting protein, which directly binds to the p53 transactivation domain, inhibits its transcriptional activity, and contributes to tumor formation and progression [7]. MDM4 can interact with MDM2 protein via the RING finger domain and inhibit degradation of the MDM2 protein, regulating the role of MDM2 in inhibiting the p53 activity [7, 8]
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