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Promoter methylation-mediated silencing of ?-catenin enhances invasiveness of non-small cell lung cancer and predicts adverse prognosis.

ABSTRACT: ?-Catenin plays dual role in adhesion complex formation and the Wnt signaling pathway. Although ?-catenin expression appears to be upregulated and Wnt signaling pathway is activated in the majority of cancers, its expression level seems to be lost in non-small cell lung cancer (NSCLC). We previously reported that the promoter of ?-catenin was hypermethylated in two NSCLC cell lines. In the current study, we expanded our analysis for the methylation status of ?-catenin promoter region and its protein expression in seven NSCLC cell lines and a series of 143 cases of primary human lung cancer with adjacent non-neoplastic tissues. Quantitative methylation specific PCR (qMSP) analysis showed methylation of ?-catenin promoter region in five NSCLC cell lines, with increased ?-catenin protein levels upon 5'-Aza-2'-deoxycytidine (5-aza-dC) treatment. The methylation status in SPC (methylated) and A549 (unmethylated) was confirmed by bisulfite sequencing PCR. 5-Aza-dC treatment inhibited invasiveness of SPC but not A549. Immunofluorescence analysis showed membranous ?-catenin expression was lost in SPC and could be re-established by 5-aza-dC, while Wnt3a treatment led to nuclear translocation of ?-catenin in both SPC and A549. Dual-luciferase assays indicated that 5-aza-dC treatment caused no significant increase in Wnt signaling activity compared with Wnt3a treatment. The effect of demethylation agent in SPC can be reversed by ?-catenin depletion but not E-cadherin depletion which indicated that the methylation mediated ?-catenin silencing might enhance NSCLC invasion and metastasis in an E-cadherin independent manner. Subsequent immunohistochemistry results further confirmed that ?-catenin promoter hypermethylation correlated with loss of immunoreactive protein expression, positive lymph node metastasis, high TNM stage and poor prognosis. The present study implicates ?-catenin promoter hypermethylation in the mechanism of epigenetic changes underlying NSCLC metastasis and progression, thus indicating the potential of ?-catenin as a novel epigenetic target for the treatment of NSCLC patients.

SUBMITTER: Miao Y

PROVIDER: S-EPMC4232381 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Promoter methylation-mediated silencing of β-catenin enhances invasiveness of non-small cell lung cancer and predicts adverse prognosis.

Miao Yuan Y Wang Liang L Zhang Xiupeng X Xu Xiaohan X Jiang Guiyang G Fan Chuifeng C Liu Yang Y Lin Xuyong X Yu Juanhan J Zhang Yong Y Wang Enhua E

PloS one 20141114 11

β-Catenin plays dual role in adhesion complex formation and the Wnt signaling pathway. Although β-catenin expression appears to be upregulated and Wnt signaling pathway is activated in the majority of cancers, its expression level seems to be lost in non-small cell lung cancer (NSCLC). We previously reported that the promoter of β-catenin was hypermethylated in two NSCLC cell lines. In the current study, we expanded our analysis for the methylation status of β-catenin promoter region and its pro ...[more]

PMID: 25396757

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Project description: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.

Dataset Information

Promoter methylation-mediated silencing of ?-catenin enhances invasiveness of non-small cell lung cancer and predicts adverse prognosis.

Publications

Promoter methylation-mediated silencing of β-catenin enhances invasiveness of non-small cell lung cancer and predicts adverse prognosis.

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