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Updated: Jun 23, 2026

Modeling Oral-Esophageal Squamous Cell Carcinoma in 3D Organoids
Published on: December 23, 2022
Global DNA hypomethylation suppresses squamous carcinogenesis in the tongue and esophagus
Seiji Baba1, Yasuhiro Yamada, Yuichiro Hatano
1Department of Tumor Pathology, Gifu University School of Medicine, Gifu, Japan.
Abstract:
Genome-wide DNA hypomethylation and concomitant site-specific gene hypermethylation are among the most common molecular alterations in human neoplasia. Previous studies revealed that genetic reduction of the DNA methylation level results in opposing effects on tumor development, depending on the tumor cell type and on the different stages of the tumorigenesis. For instance, reduced levels of DNA methylation in mice strongly inhibited tumor development of the intestine, whereas they induced thymic lymphomas and liver tumors. In the present study, using DNA methyltrasferase 1 (Dnmt1) hypomorphic alleles to reduce genomic methylation, we examined the effects of DNA hypomethylation on a murine squamous carcinogenesis in the tongue and esophagus induced by 4-nitroquinoline 1-oxide. Genetic reduction of DNA methylation level led to the suppression of tumor formation in both tongue and esophagus. Histological analyses revealed that DNA hypomethylation preferentially inhibited the development of squamous cell carcinomas. The results suggest that genomic hypomethylation inhibits squamous carcinogenesis in the tongue and esophagus, and that pharmacological modification of epigenetic status might be useful for the prevention and treatment of cancers in the upper digestive tract.
Insights
Reducing DNA methylation (hypomethylation) suppressed squamous cell carcinoma development in mouse tongues and esophagi. This suggests epigenetic modifications could aid in preventing and treating upper digestive tract cancers.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- Genome-wide DNA hypomethylation and site-specific hypermethylation are common in human cancers.
- Reduced DNA methylation has variable effects on tumor development, depending on cell type and cancer stage.
Purpose of the Study:
- To investigate the impact of DNA hypomethylation on squamous carcinogenesis in the tongue and esophagus.
- To assess the role of DNA methyltransferase 1 (Dnmt1) in this process.
Main Methods:
- Utilized DNA methyltransferase 1 (Dnmt1) hypomorphic alleles to genetically reduce genomic methylation levels in mice.
- Induced squamous carcinogenesis using 4-nitroquinoline 1-oxide in the tongue and esophagus.
- Performed histological analyses to evaluate tumor development and type.
Main Results:
- Genetic reduction of DNA methylation significantly suppressed tumor formation in both the tongue and esophagus.
- DNA hypomethylation preferentially inhibited the development of squamous cell carcinomas.
- The findings indicate a protective role of hypomethylation against squamous carcinogenesis in these tissues.
Conclusions:
- Genomic hypomethylation inhibits squamous carcinogenesis in the tongue and esophagus.
- Pharmacological manipulation of epigenetic status may offer a strategy for preventing and treating upper digestive tract cancers.
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