Reduction of pancreatic acinar cell tumor multiplicity in Dnmt1 hypomorphic mice
Shirley Oghamian1, Nicole M Sodir, Muhammad U Bashir
1Department of Surgery, USC/Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA 90089-9176, USA.
Abstract:
In human pancreatic cancers, promoter CpG island hypermethylation is observed in both benign and malignant tumors. It is thought that silencing of key growth-controlling genes by promoter hypermethylation may play a role in pancreatic oncogenesis. We have shown previously that sufficient levels of DNA methyltransferase (Dnmt) 1 expression are required for the development of murine intestinal tumors. Here, we report the results of a large-scale triple cross (progeny n = 761) between Apc(Min/+), Trp53(-/-) and Dnmt1 hypomorphic mice to investigate the role of Dnmt levels in the Apc(Min/+), Trp53(-/-) mouse models of acinar cell pancreatic cancer. Mutations of both APC and TP53 are observed in human pancreatic cancer. We found that tumor burden, but not tumor size, is significantly reduced with decreasing Dnmt1 levels, suggesting that DNA methylation is involved in pancreatic tumorigenesis in this mouse model. Detailed analyses showed that the reduction in tumor burden is the result of a decrease in both early- and late-stage lesions. We observed decreased levels of DNA methylation at candidate genes in the normal pancreas of Dnmt1 hypomorphic mice. Some of these genes showed increased methylation associated with tumorigenesis, suggesting that the tumor-suppressive effects of Dnmt1 hypomorphic alleles may be mediated in part through reduced promoter hypermethylation. Our work is the first in vivo study to show the effects of reduced Dnmt levels on pancreatic tumor development.
Insights
Decreased DNA methyltransferase (Dnmt1) levels reduce pancreatic tumor burden in mice. This suggests DNA methylation plays a key role in pancreatic cancer development and offers potential therapeutic targets.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- CpG island hypermethylation is common in human pancreatic cancers, potentially silencing growth-controlling genes.
- DNA methyltransferase (Dnmt) 1 is crucial for murine intestinal tumor development.
- APC and TP53 mutations, observed in human pancreatic cancer, are present in the mouse models used.
Purpose of the Study:
- To investigate the role of DNA methyltransferase (Dnmt) 1 levels in pancreatic cancer development.
- To examine the impact of Dnmt1 levels on Apc(Min/+), Trp53(-/-) mouse models of pancreatic cancer.
Main Methods:
- A large-scale triple cross of Apc(Min/+), Trp53(-/-), and Dnmt1 hypomorphic mice (n=761).
- Analysis of tumor burden and size in relation to Dnmt1 levels.
- Assessment of DNA methylation patterns in normal and tumor tissues.
Main Results:
- Decreasing Dnmt1 levels significantly reduced pancreatic tumor burden, but not tumor size.
- The reduction in tumor burden resulted from fewer early- and late-stage lesions.
- Dnmt1 hypomorphic mice showed decreased DNA methylation in candidate genes, with some showing increased methylation during tumorigenesis.
Conclusions:
- Reduced Dnmt1 levels suppress pancreatic tumor development in this mouse model.
- DNA methylation, specifically promoter hypermethylation, is implicated in pancreatic tumorigenesis.
- This study provides the first in vivo evidence linking reduced Dnmt levels to pancreatic tumor development.
