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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.


PROVIDER: S-EPMC4232381 | BioStudies | 2014-01-01

REPOSITORIES: biostudies

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