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Updated: Jun 10, 2026
Genome-Wide Analysis of DNA Methylation in Gastrointestinal Cancer
Published on: September 18, 2020
Identification of GPX3 epigenetically silenced by CpG methylation in human esophageal squamous cell carcinoma
Yuanlong He1, Yongjun Wang, Peng Li
1Department of Gastroenterology, Beijing Friendship Hospital Affiliated to the Capital Medical University, Beijing Digestive Disease Center, 95 Yong'an Road, 100050, Beijing, People's Republic of China. hylqz@yahoo.cn
Background:
Esophageal squamous cell carcinoma (ESCC) is one of the most common causes of cancer mortality in the gastrointestinal tract. Promoter hypermethylation of tumor suppressor genes contributes to gene inactivation during development of ESCC.
Aim:
To identify novel methylation-silenced genes in ESCC.
Methods:
Genome-wide microarrays were applied to search for genes that were markedly upregulated after treatment with 5-aza-2'-deoxycytidine (5-Aza-dC) and that were markedly decreased in tumor tissue compared with paired adjacent nontumor tissue. Reverse-transcription polymerase chain reaction (PCR), immunohistochemistry, methylation-specific PCR, and bisulfite genomic sequencing were employed to investigate expression and methylation of candidate genes in five human ESCC cell lines, two human immortalized normal esophageal epithelial cell lines, primary ESCC tumor tissues, and paired adjacent nontumor tissues.
Results:
GPX3 was selected as a novel candidate hypermethylated gene in ESCC through microarray analysis. In most ESCC cell lines, GPX3 messenger RNA (mRNA) expression was downregulated and the CpG island of GPX3 promoter was methylated. Demethylation treatment with 5-Aza-dC restored GPX3 mRNA expression. Methylation of GPX3 promoter was more frequent in ESCC tumor tissues (71.4%) than in adjacent nontumor tissues (10.7%) (P < 0.001), and methylation of GPX3 promoter correlated significantly with GPX3 mRNA downregulation. Finally, GPX3 protein expression was also significantly lower in ESCC tumor tissues than in adjacent nontumor tissues.
Conclusion:
GPX3 is downregulated through promoter hypermethylation in ESCC, which may be a potential biomarker of ESCC.
Insights
Glutathione peroxidase 3 (GPX3) is silenced by promoter hypermethylation in esophageal squamous cell carcinoma (ESCC). This epigenetic silencing leads to reduced GPX3 expression, suggesting GPX3 as a potential biomarker for ESCC.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- Esophageal squamous cell carcinoma (ESCC) is a leading cause of cancer death.
- Promoter hypermethylation of tumor suppressor genes is a key mechanism in ESCC development.
Purpose of the Study:
- To identify novel genes silenced by methylation in ESCC.
- To investigate the role of glutathione peroxidase 3 (GPX3) in ESCC pathogenesis.
Main Methods:
- Genome-wide microarrays identified genes upregulated by 5-aza-2'-deoxycytidine (5-Aza-dC) and downregulated in tumor tissue.
- Reverse-transcription PCR, immunohistochemistry, and methylation-specific PCR validated GPX3 expression and methylation status.
- Analysis was performed in ESCC cell lines, normal esophageal cell lines, and primary tumor tissues.
Main Results:
- GPX3 was identified as a novel hypermethylated gene in ESCC.
- GPX3 messenger RNA (mRNA) expression was significantly downregulated in ESCC cell lines and tumor tissues.
- GPX3 promoter hypermethylation was frequent in ESCC tumors (71.4%) compared to adjacent tissues (10.7%) and correlated with reduced mRNA expression.
- GPX3 protein levels were also significantly lower in ESCC tumors.
Conclusions:
- GPX3 is epigenetically silenced by promoter hypermethylation in ESCC.
- GPX3 downregulation is a common event in ESCC development.
- GPX3 represents a potential diagnostic biomarker for esophageal squamous cell carcinoma.
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