Department of Surgery, USC/Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA 90089-9176, USA.
Carcinogenesis. 2011 Jun;32(6):829-35. doi: 10.1093/carcin/bgr039. Epub 2011 Mar 1.
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.
在人类胰腺癌中，良性和恶性肿瘤均观察到启动子 CpG 岛甲基化过度。据认为，启动子甲基化导致关键生长调控基因失活可能在胰腺发生中起作用。我们之前已经表明，DNA 甲基转移酶 (Dnmt) 1 的表达水平足以发展为小鼠的肠道肿瘤。在这里，我们报告了 Apc(Min/+)、Trp53(-/-)和 Dnmt1 低功能小鼠之间的大规模三交 (后代 n = 761) 的结果，以研究 Dnmt 水平在 Apc(Min/+)、Trp53(-/-)小鼠胰腺腺泡细胞癌模型中的作用。人类胰腺癌中观察到 APC 和 TP53 的突变。我们发现，随着 Dnmt1 水平的降低，肿瘤负担而非肿瘤大小显著降低，这表明 DNA 甲基化参与了该小鼠模型中的胰腺肿瘤发生。详细分析表明，肿瘤负担的降低是早期和晚期病变减少的结果。我们观察到 Dnmt1 低功能小鼠正常胰腺中候选基因的 DNA 甲基化水平降低。这些基因中的一些显示出与肿瘤发生相关的甲基化增加，这表明 Dnmt1 低功能等位基因的肿瘤抑制作用可能部分通过减少启动子过度甲基化来介导。我们的工作是首次在体内研究表明降低 Dnmt 水平对胰腺肿瘤发展的影响。
