A sequence variant in the phospholipase C epsilon C2 domain is associated with esophageal carcinoma and esophagitis

Abstract

A single-nucleotide polymorphism (rs2274223: A5780G:His1927Arg) in the phospholipase C epsilon gene (PLCε) was recently identified as a susceptibility locus for esophageal cancer in Chinese subjects. To determine the underlying mechanisms of PLCε and this SNP in esophageal carcinogenesis, we analyzed PLCε genotypes, expression, and their correlation in esophageal cancer cell lines, non-transformed esophageal cells, 58 esophageal squamous cell carcinomas and 10,614 non-cancer subjects from China. We found that the G allele (AG or GG) was associated with increased PLCε mRNA and protein expression in esophageal cancer tissues and in esophageal cancer cell lines. G allele was also associated with higher enzyme activity, which might be associated with increased protein expression. Quantitative analysis of the C2 domain sequences revealed that A:G allelic imbalance was strongly linked to esophageal malignancy. Moreover, the analysis of 10,614 non-cancer subjects demonstrated that the G allele was strongly associated with moderate to severe esophagitis in the subjects from the high-incidence areas of China (OR 6.03, 95% CI 1.59–22.9 in high-incidence area vs. OR 0.74, 95% CI 0.33–1.64 in low-incidence area; P = 0.008). In conclusion, the PLCε gene, particularly the 5780G allele, might play a pivotal role in esophageal carcinogenesis via upregulating PLCε mRNA, protein, and enzyme activity, and augmenting inflammatory process in esophageal epithelium. Thus, 5780G allele may constitute a promising biomarker for esophageal squamous cell carcinoma risk stratification, early detection, and progression prediction.

PLCE1 mRNA and Protein Expression and Survival of Patients with Esophageal Squamous Cell Carcinoma and Gastric Adenocarcinoma

“…Our results are similar to the report from Shanghai (24), but contrast with studies from the other two groups (25-26). Our observations of reduced PLCE1 expression in GCA and GNCA are also discrepant from other reported studies (7,27).…”

“…In a third study, Wang et al showed increased protein expression in both ESCC and GCA tissues compared to normal tissues (n=94 for ESCC, and n=13 for GCA)(7). This same group also recently reported that PLCE1 mRNA was significantly higher in ESCC tumors than in matched normal tissues (n=26)(26). In all of the above-mentioned studies, mRNA was assayed by real-time RT-PCR, while protein was assayed by immunohistochemistry.…”

“…Previous studies conducted among Chinese have reported differential PLCE1 mRNA and protein expression between ESCC tumors and normal tissues, but with conflicting results (24-26). A study in Shanghai observed decreased PLCE1 mRNA in ESCC tumors compared with matched normal esophagus (n=36), but no change in protein expression (n=39, including the 36 cases tested for mRNA) (24).…”

Phospholipase C ε‑1 gene polymorphisms and prognosis of esophageal cancer patients from a high‑incidence region in northern China

“…Two studies demonstrated that the PLCE1 rs2274223 SNP was associated with the risk of ESCC (3,10). Subsequently, Wang et al investigated the PLCE1 protein expression of ESCC tissues with different genotypes of rs2274223 SNP and found a higher expression level in ESCC tissues with the A/G genotype compared with those with the A/A genotype (28). Similar results were observed in the study by Hu et al (10).…”

“…Hu et al (10) and Li et al (24) reported decreased mRNA in ESCC tumors compared with that in the adjacent normal esophagus, but no difference in protein expression. By contrast, ESCC tissues exhibited a higher PLCE1 protein expression compared with normal tissues in other studies (3,23,(28)(29)(30). This disparity may be attributed to differences in sample size, genetic background or experimental methods.…”