Abstract
BackgroundGastric cancer (GC) is one of the most significant health problems worldwide. Some studies have reported associations between Phospholipase C epsilon 1 (PLCE1) single-nucleotide polymorphisms (SNPs) and GC susceptibility, but its relationship with GC prognosis lacked exploration, and the specific mechanisms were not elaborated fully yet. This study aimed to further explore the possible mechanism of the association between PLCE1 polymorphisms and GC.Materials and MethodsA case-control study, including 588 GC patients and 703 healthy controls among the Chinese Han population, was performed to investigate the association between SNPs of PLCE1 and GC risk by logistic regression in multiple genetic models. The prognostic value of PLCE1 in GC was evaluated by the Kaplan-Meier plotter. To explored the potential functions of PLCE1, various bioinformatics analyses were conducted. Furthermore, we also constructed the spatial structure of PLCE1 protein using the homology modeling method to analyze its mutations.ResultsRs3765524 C > T, rs2274223 A > G and rs3781264 T > C in PLCE1 were associated with the increased risk of GC. The overall survival and progression-free survival of patients with high expression of PLCE1 were significantly lower than those with low expression [HR (95% CI) = 1.38 (1.1–1.63), P < 0.01; HR (95% CI) = 1.4 (1.07–1.84), P = 0.01]. Bioinformatic analysis revealed that PLCE1 was associated with protein phosphorylation and played a crucial role in the calcium signal pathway. Two important functional domains, catalytic binding pocket and calcium ion binding pocket, were found by homology modeling of PLCE1 protein; rs3765524 polymorphism could change the efficiency of the former, and rs2274223 polymorphism affected the activity of the latter, which may together play a potentially significant role in the tumorigenesis and prognosis of GC.ConclusionPatients with high expression of PLCE1 had a poor prognosis in GC, and SNPs in PLCE1 were associated with GC risk, which might be related to the changes in spatial structure of the protein, especially the variation of the efficiency of PLCE1 in the calcium signal pathway.
Highlights
Gastric cancer (GC) is becoming a worldwide problem year by year, endangering human life and health severely
This study aimed to analyze the relationship between three single nucleotide polymorphism (SNP) in the Phospholipase C epsilon 1 (PLCE1) gene and GC susceptibility by a case-control study in the Chinese Han population firstly; we explored the prognostic value of PLCE1 in GC using online databases; we tried to explain the correlation mechanism between the SNPs in PLCE1 and the risk and prognosis of GC from the perspective of variable bioinformatics and protein spatial structure changes
We used SWISS-MODEL5 to perform PLCE1 protein homology-modeling from its primary sequence (Schwede et al, 2003; Waterhouse et al, 2018)
Summary
Gastric cancer (GC) is becoming a worldwide problem year by year, endangering human life and health severely. The genomic analysis of gastric tumors has highlighted the importance of its gene heterogeneity; and differentiations of GC molecular subtypes may be the key to guiding early diagnosis strategies, identifying new therapeutic targets, and predicting the prognosis of patients. Single nucleotide polymorphism (SNP) analysis has been extensively used to screen candidate gene and detect various complex human diseases, providing a way to identify genetic loci associated with the heterogeneity of cancers. Some studies have reported associations between Phospholipase C epsilon 1 (PLCE1) single-nucleotide polymorphisms (SNPs) and GC susceptibility, but its relationship with GC prognosis lacked exploration, and the specific mechanisms were not elaborated fully yet. This study aimed to further explore the possible mechanism of the association between PLCE1 polymorphisms and GC
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