We demonstrated that in the Apc1638N mouse genetic model of intestinal tumorigenesis, introduction of a targeted inactivation of a single p2iWAF1/clp1 allele was sufficient to both enhance tumor formation and eliminate the ability of sulindac to inhibit tumor formation (Yang et al, Cancer Res, 61, 565, 2001 a; Yang et al, Cancer Res. 61, 6297, 2001 b). We have newfound that the reason for the apparent haplo-insufficiency of p21 in both tumor suppression, and in the chemopreventive response to sulindac, is because the remaining wild-type p21 allele is functionally inactivated by methylation of CpG island in its promoter. It is therefore not expressed, and cannot be induced by sulindac.
In aim 1, we will determine the mechanism of this inactivation of p21 by promoter methylation by: determining whether the methylation of the wild-type allele in p21 mice is dependent on heterozygosity of the Ape gene; dissecting how the sites of altered methylation in the promoter correspond to cis-acting elements necessary for the response of p21 to sulindac; and assaying the role of altered expression and levels of DNA methyltransferases in the modulation of p21 methylation.
Aim 2 will investigate how selenium, a nutritional preventive agent, reported to cause DNA hypomethylation, and a pharmacological demethylating agent, Decitabine (2'-deoxy-5'-azacytidine), lter methylation of the wild-type allele in the Apc, p21 mice, and restore tumor suppression activity and response to sulindac. Further, we will use gene expression profiling, quantitative real time RT-PCR, and assays of methylation of the Ape, Mlh1 and Muc2 genes, to understand the similarities and differences in the affects of the nutritional and pharmacological agents, and the extent to which altered CpG island methylation at specific loci is translated into altered gene expression.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA112081-05
Application #
7417637
Study Section
Special Emphasis Panel (ZRG1-CDP (01))
Program Officer
Perloff, Marjorie
Project Start
2005-06-01
Project End
2010-04-30
Budget Start
2008-05-01
Budget End
2009-04-30
Support Year
5
Fiscal Year
2008
Total Cost
$232,210
Indirect Cost
Name
University of Illinois at Chicago
Department
Pathology
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Wang, Li-Dong; Bi, Xiuli; Song, Xin et al. (2013) A sequence variant in the phospholipase C epsilon C2 domain is associated with esophageal carcinoma and esophagitis. Mol Carcinog 52 Suppl 1:E80-6
Bi, Xiuli; Pohl, Nicole; Dong, Huali et al. (2013) Selenium and sulindac are synergistic to inhibit intestinal tumorigenesis in Apc/p21 mice. J Hematol Oncol 6:8
Bi, Xiuli; Pohl, Nicole M; Qian, Zhibin et al. (2012) Decorin-mediated inhibition of colorectal cancer growth and migration is associated with E-cadherin in vitro and in mice. Carcinogenesis 33:326-30
Bi, Xiuli; Pohl, Nicole M; Yin, Zhinan et al. (2011) Loss of JNK2 increases intestinal tumor susceptibility in Apc1638+/- mice with dietary modulation. Carcinogenesis 32:584-8
Tong, Yunguang; Yang, Wancai; Koeffler, H Phillip (2011) Mouse models of colorectal cancer. Chin J Cancer 30:450-62
Fang, Wenfeng; Goldberg, Marci L; Pohl, Nicole M et al. (2010) Functional and physical interaction between the selenium-binding protein 1 (SBP1) and the glutathione peroxidase 1 selenoprotein. Carcinogenesis 31:1360-6
Bi, Xiuli; Fang, Wenfeng; Wang, Li-Shu et al. (2010) Black raspberries inhibit intestinal tumorigenesis in apc1638+/- and Muc2-/- mouse models of colorectal cancer. Cancer Prev Res (Phila) 3:1443-50
Fang, Wenfeng; Han, Anjia; Bi, Xiuli et al. (2010) Tumor inhibition by sodium selenite is associated with activation of c-Jun NH2-terminal kinase 1 and suppression of beta-catenin signaling. Int J Cancer 127:32-42
Pohl, Nicole M; Tong, Chang; Fang, Wenfeng et al. (2009) Transcriptional regulation and biological functions of selenium-binding protein 1 in colorectal cancer in vitro and in nude mouse xenografts. PLoS One 4:e7774
Hu, Dong; Bi, Xiuli; Fang, Wenfeng et al. (2009) GSK3beta is involved in JNK2-mediated beta-catenin inhibition. PLoS One 4:e6640

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