Description of Research Expertise

Research Interests
Coordination of development and proliferation in the intestinal crypt and its dysregulation in carcinogenesis.
Mechanisms of cell-cell adhesion, and its role in intestinal epithelial cell development.
Cdx modulation of beta-catenin transcriptional and cell-cell adhesion activity in intestinal cells.
Mechanisms of intestinal metaplasia of the esophagus and stomach.

Description of Research

Primary Focus:
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 a third of them will ultimately die from their disease. Abnormal regulation of beta-catenin levels and function commonly occurs during colon carcinogenesis. beta-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 beta-catenin can thus endow a cancer cell with many of the features necessary for colon carcinogenesis. The mechanisms by which normal intestinal cells regulate beta-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. It's role in promoting intestinal cell differentiation and regulating proliferation is recognized but the mechanism remains unknown. Our research has specifically investigated these processes. We found that expression of Cdx2 inhibited beta-catenin/TCF transcriptional activity.
Moreover, cancer cells were relatively resistant to Cdx2's effect on beta_catenin/TCF, when compared with it's homologue Cdx1. In addition, we have developed a cell culture system to model Cdx2 induction of a polarized, columnar cell morphology in human colonocytes. This effect requires a functioning E-cadherin/beta-catenin complex, and involves post-translation modifications of beta-catenin. Current research is focused on characterizing the proliferation and cell-adhesion effects of Cdx2 on intestinal epithelial and cancer cells. Specifically we are testing the following hypothesis: Cdx2 inhibits colonocyte proliferation and promotes morphologic maturation by modulating beta-catenin transcriptional and cell-cell adhesion activity. Our work therefore explores a possible role 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 greatly improve our knowledge of the events occurring normally in colonic crypts as well as enhance our understanding of the events leading to dysregulation of proliferation and differentiation in human colon cancers.

Secondary Focus:
Esophageal adenocarcinoma (EAC) has been the fastest rising malignancy in the U.S.. Several conditions increase the risk for the development of EAC, including obesity, smoking, diet, acid reflux, and, most significantly, Barrett's esophagus (BE). BE occurs at the gastroesophageal (GE) junction and is the replacement of normal squamous esophageal mucosa with an intestinalized columnar epithelium. It typically arises in response to chronic acid exposure and is associated with acid reflux. Importantly, the molecular mechanisms underpinning the establishment of Barrett's metaplasia are not understood. Moreover, no experimental cell-culture or animal models exist for this condition. Ectopic expression of intestine-specific transcription factors is characteristic of BE. The homeodomain transcription factor Cdx2 is an important regulator of intestine-specific gene expression. It is expressed ectopically in BE, but its role is unknown. Our research has investigated this role. We hypothesize that ectopic Cdx2 expression synergises with acid reflux, COX-2 overexpression, tumor-suppressor p53 mutations, and/or alterations in DNA methylation patterns to promote intestinal transdifferentiation of keratinocytes. We will test this hypothesis by developing cell-culture and transgenic mouse models for intestinal metaplasia.

Rotation projects for 2006-2007

Mechanisms of beta-catenin inhibition by Cdx2--biochemical and mutagenesis approaches
Cell-cell adhesion induced by Cdx2 in colon cancer cells--cadherins, desmocollin, and integrins
Animal and cell culture models of Barrett's metaplasia

Lab personnel:
Rong Jun Guo MD PhD--Post Doc
Jianping Kong PhD--Post Doc
Sanjay Hegde MD-Post Doc
Shinsuke Funakoshi MD-Visiting Scholar
Hong Li--Research specialist
Hoeun Lee-Technician