Methylation of the claudin‑3 promoter predicts the prognosis of advanced gastric adenocarcinoma

Zhang,Zhenzhen; Yu,Weixing; Chen,Shuqin; Chen,Yupeng; Chen,Linying; Zhang,Sheng

doi:10.3892/or.2018.6411

Methylation of the claudin‑3 promoter predicts the prognosis of advanced gastric adenocarcinoma

Authors:
- Zhenzhen Zhang
- Weixing Yu
- Shuqin Chen
- Yupeng Chen
- Linying Chen
- Sheng Zhang
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Affiliations: Department of Pathology, The First Affiliated Hospital of Fujian Medical University, Fujian, Fuzhou 350005, P.R. China, Institute of Translational Medicine, Fujian Medical University, Fujian, Fuzhou 350122, P.R. China, Department of Pathology, Fujian Medical University, Fujian, Fuzhou 350122, P.R. China
Published online on: May 2, 2018 https://doi.org/10.3892/or.2018.6411
Pages: 49-60
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Claudin‑3 expression is associated with gastric cancer progression, but the role of epigenetic modifications remains unclear. We investigated methylation of the claudin‑3 promoter and expression profiles in gastric adenocarcinoma and their associations with clinicopathological characteristics and prognosis of the patients. A total of 122 patients with advanced gastric cancer [stage IIB‑IV, with lymph node (LN) metastasis] were enrolled. Each patient provided 4 tissue samples: normal gastric epithelium, intestinal metaplasia, primary tumor and metastatic LN. Claudin‑3 protein expression was examined by immunohistochemistry. Claudin‑3 promoter methylation was determined by methylation‑specific PCR and verified by bisulfite sequencing PCR. Claudin‑3 mRNA expression was measured by real‑time PCR in a subset of cases, and its correlation with protein expression was analyzed using Spearman correlation. Kaplan‑Meier survival analysis was performed (log‑rank test). Factors associated with survival were identified by Cox regression. The strong expression rate of claudin‑3 in intestinal metaplasia, primary tumor, metastatic LN and normal gastric epithelium was 91.8, 58.2, 30.3 and 13.9%, respectively. The promoter hypermethylation rate in intestinal metaplasia, primary tumor, normal gastric epithelium and metastatic LN was 5.7, 27.9, 36.9 and 49.2%, respectively. Claudin‑3 mRNA and protein expression were positively correlated (P<0.001) with normal gastric epithelium (rs=0.745), intestinal metaplasia (rs=0.876), primary gastric adenocarcinoma (rs=0.915) and metastatic LN (rs=0.819). Claudin‑3 mRNA expression was negatively correlated with claudin‑3 promoter methylation. Median patient survival was 38, 22 and 11 months in the hypomethylated, partially methylated and hypermethylated groups, respectively (P<0.001). Claudin‑3 promoter methylation status (HR: 5.67; 95% CI: 2.27‑14.17) but not claudin‑3 expression was an independent predictor of survival. Claudin‑3 promoter hypermethylation reduces claudin‑3 expression and independently predicts poor prognosis.

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