J Cancer 2014; 5(6):457-464. doi:10.7150/jca.9145

Research Paper

Regulation of Desmocollin3 Expression by Promoter Hypermethylation is Associated with Advanced Esophageal Adenocarcinomas

Qinggang Wang1,2, DunFa Peng2, Shoumin Zhu2, Zheng Chen2,3, TianLing Hu2, Mohammed Soutto2, Rama Saad2,4, Shutian Zhang1✉, Wael EI-Rifai2,5✉

1. Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing China;
2. Department of Surgery, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA;
3. Department of General Surgery; The First Affiliated Hospital of Nanjing Medical University, Nanjing, China;
4. Department of Biology, The American University in Cairo, Cairo, Egypt;
5. Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

Abstract

BACKGROUND: Desmocollin3 (DSC3) is a member of the cadherin superfamily of calcium-dependent cell adhesion molecules and plays an important role in tumor invasion and metastasis. In this study, we investigated the epigenetic mechanism that regulates DSC3 expression in esophageal adenocarcinomas (EACs). METHODS: Expression of DSC3 was analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). The promoter DNA methylation level of DSC3 was examined using quantitative bisulfite pyrosequencing. RESULTS: The qRT-PCR analysis demonstrated significant down-regulation of the DSC3 mRNA levels in human EAC cell lines and tissue samples (P<.001). In addition, the EAC cell lines and tumor samples have aberrant promoter hypermethylation as compared to normal esophageal samples (P<.001). DSC3 promoter hypermethylation (>10% methylation level) was detected in 97.5% (39/40) of EAC samples whereas none of the normal tissue samples showed hypermethylation (P<.0001). There was a significant inverse correlation between promoter DNA methylation levels and mRNA expression folds for DSC3 (coefficient r=-0.685, P<.0001). Treatment of FLO-1 and SKGT4 EAC cells with 5-Aza-deoxytidine led to a significant reduction in the promoter DNA methylation levels with restoration of the DSC3 expression, suggesting that promoter DNA methylation is a key epigenetic mechanism regulating DSC3 expression. High DSC3 promoter DNA methylation levels were significantly correlated with advanced tumor stage (P<.001) and lymph node metastasis (P<.001). CONCLUSION: Taken together, our results demonstrate that epigenetic silencing of DSC3 is a frequent finding in EAC that is possibly associated with advanced stages.

Keywords: epigenetics, DSC3, esophageal, cancer, metastasis.

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How to cite this article:
Wang Q, Peng D, Zhu S, Chen Z, Hu T, Soutto M, Saad R, Zhang S, EI-Rifai W. Regulation of Desmocollin3 Expression by Promoter Hypermethylation is Associated with Advanced Esophageal Adenocarcinomas. J Cancer 2014; 5(6):457-464. doi:10.7150/jca.9145. Available from http://www.jcancer.org/v05p0457.htm