Colon cancer is an important cause of cancer mortality. In the United States, over 150,000 people are newly diagnosed with this disease each year, and one-third of them will ultimately die from their disease. Abnormal regulation of p-catenin levels and function commonly occur during colon carcinogenesis. p-catenin is a multifunctional protein with known roles in enhancing proliferation, inhibiting intestinal cell differentiation and apoptosis, and regulating cell-cell adhesion, angiogenesis, and cell migration. Dysregulation of p-catenin can thus endow a cancer cell with many of the features necessary for colon carcinogenesis. The molecular mechanisms by which normal intestinal cells regulate p-catenin function, and by which cancer cells abrogate this regulation, are not understood. The homeodomain transcription factor Cdx2 is a well-studied regulator of intestine-specific gene expression. Its role in promoting intestinal cell differentiation and regulating proliferation is recognized but the mechanisms remain to be elucidated. Our research has specifically investigated these processes. We have found that Cdx2 inhibits p-catenin/TCF transcriptional activity. Moreover, cancer cells were relatively resistant to Cdx2's effect on p-catenin/TCF. In addition, we have developed a cell culture system to model Cdx2 induction of a polarized, columnar cell morphology in human colonocytes, a novel mechanism attributable to Cdx2. This effect requires a functional E-cadherin/p-catenin complex, and accompanying post- translational modifications of p-catenin. This proposal is directed towards characterizing Cdx2 mediated biological effects upon proliferation and cell-adhesion and will test the following overarching hypothesis: Cdx2 inhibits colonocvte proliferation and promotes morphologic maturation by modulating B-catenin transcriptional and cell-cell adhesion activity. This hypothesis will be pursued by the following inter-related Specific Aims: (1) To investigate the inhibition of p- catenin mediated proliferation by Cdx2, and the resistance to this inhibitory effect in colon cancer cells;and, (2) To characterize the molecular mechanisms for Cdx2-mediated cell-cell adhesion and columnar morphogenesis. This proposal therefore explores the novel roles for Cdx2 in regulating the interdependent processes of cell-cell adhesion, acquisition of a polarized and columnar morphology, and cell-proliferation within the colonocyte. Understanding these mechanisms will improve greatly our knowledge of the molecular events governing normal colonocyte biology, and simultaneously, provide new insights into the molecular pathogenesis of sporadic colon cancer. As a result, potential novel targeted therapeutics mayalso emerge.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Gastrointestinal Cell and Molecular Biology Study Section (GCMB)
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Carrington, Jill L
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University of Pennsylvania
Internal Medicine/Medicine
Schools of Medicine
United States
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Kong, Jianping; Crissey, Mary Ann S; Stairs, Douglas B et al. (2011) Cox2 and ?-catenin/T-cell factor signaling intestinalize human esophageal keratinocytes when cultured under organotypic conditions. Neoplasia 13:792-805
Kong, Jianping; Crissey, Mary Ann; Funakoshi, Shinsuke et al. (2011) Ectopic Cdx2 expression in murine esophagus models an intermediate stage in the emergence of Barrett's esophagus. PLoS One 6:e18280
Crissey, Mary Ann S; Guo, Rong-Jun; Funakoshi, Shinsuke et al. (2011) Cdx2 levels modulate intestinal epithelium maturity and Paneth cell development. Gastroenterology 140:517-528.e8
Verzi, Michael P; Hatzis, Pantelis; Sulahian, Rita et al. (2010) TCF4 and CDX2, major transcription factors for intestinal function, converge on the same cis-regulatory regions. Proc Natl Acad Sci U S A 107:15157-62
Huo, Xiaofang; Zhang, Hui Ying; Zhang, X I et al. (2010) Acid and bile salt-induced CDX2 expression differs in esophageal squamous cells from patients with and without Barrett's esophagus. Gastroenterology 139:194-203.e1
Guo, Rong-Jun; Funakoshi, Shinsuke; Lee, Hannah H et al. (2010) The intestine-specific transcription factor Cdx2 inhibits beta-catenin/TCF transcriptional activity by disrupting the beta-catenin-TCF protein complex. Carcinogenesis 31:159-66
Stairs, Douglas B; Kong, Jianping; Lynch, John P (2010) Cdx genes, inflammation, and the pathogenesis of intestinal metaplasia. Prog Mol Biol Transl Sci 96:231-70
Funakoshi, Shinsuke; Kong, Jianping; Crissey, Mary Ann et al. (2010) Intestine-specific transcription factor Cdx2 induces E-cadherin function by enhancing the trafficking of E-cadherin to the cell membrane. Am J Physiol Gastrointest Liver Physiol 299:G1054-67
Kong, Jianping; Stairs, Douglas B; Lynch, John P (2010) Modelling Barrett's oesophagus. Biochem Soc Trans 38:321-6
Kong, Jianping; Nakagawa, Hiroshi; Isariyawongse, Brandon K et al. (2009) Induction of intestinalization in human esophageal keratinocytes is a multistep process. Carcinogenesis 30:122-30

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