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Open Access Research article

Temporal evolution in caveolin 1 methylation levels during human esophageal carcinogenesis

Zhe Jin1345*, Liang Wang14, Ziyi Cao1, Yulan Cheng2, Yan Gao6, Xianling Feng1, Si Chen1, Huimin Yu1, Wenjing Wu2, Zhenfu Zhao1, Ming Dong1, Xiaojing Zhang14, Jie Liu1, Xinmin Fan1, Yuriko Mori2 and Stephen J Meltzer2*

Author Affiliations

1 Department of Pathology, The Shenzhen University School of Medicine, 3688 Nanhai Ave, Rm 703, Nanshan, Shenzhen 518060, Guangdong, People’s Republic of China

2 Division of Gastroenterology, Department of Medicine, The Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA

3 Shenzhen Key Laboratory of Micromolecule Innovatal Drugs, The Shenzhen University School of Medicine, Shenzhen, Guangdong, People’s Republic of China

4 Shenzhen Key Laboratory of translational Medicine of Tumor, the Shenzhen University School of Medicine, Shenzhen, Guangdong, People’s Republic of China

5 Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, Guangdong, People’s Republic of China

6 Nanshan Hospital, Guangdong Medical College, Shenzhen, People’s Republic of China

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BMC Cancer 2014, 14:345  doi:10.1186/1471-2407-14-345

Published: 20 May 2014

Abstract

Background

Esophageal cancer ranks eighth among frequent cancers worldwide. Our aim was to investigate whether and at which neoplastic stage promoter hypermethylation of CAV1 is involved in human esophageal carcinogenesis.

Methods

Using real-time quantitative methylation-specific PCR (qMSP), we examined CAV1 promoter hypermethylation in 260 human esophageal tissue specimens. Real-time RT-PCR and qMSP were also performed on OE33 esophageal cancer cells before and after treatment with the demethylating agent, 5-aza-2’-deoxycytidine (5-Aza-dC).

Results

CAV1 hypermethylation showed highly discriminative ROC curve profiles, clearly distinguishing esophageal adenocarcinomas (EAC) and esophageal squamous cell carcinomas (ESCC) from normal esophagus (NE) (EAC vs. NE, AUROC = 0.839 and p < 0.0001; ESCC vs. NE, AUROC = 0.920 and p < 0.0001). Both CAV1 methylation frequency and normalized methylation value (NMV) were significantly higher in Barrett’s metaplasia (BE), low-grade and high-grade dysplasia occurring in BE (D), EAC, and ESCC than in NE (all p < 0.01, respectively). Meanwhile, among 41 cases with matched NE and EAC or ESCC, CAV1 NMVs in EAC and ESCC (mean = 0.273) were significantly higher than in corresponding NE (mean = 0.146; p < 0.01, Student’s paired t-test). Treatment of OE33 EAC cells with 5-Aza-dC reduced CAV1 methylation and increased CAV1 mRNA expression.

Conclusions

CAV1 promoter hypermethylation is a frequent event in human esophageal carcinomas and is associated with early neoplastic progression in Barrett’s esophagus.

Keywords:
CAV1; Hypermethylation; EAC; ESCC