Adenocarcinoma of the colon is the third-leading malignancy in the U.S. and ranks second only to lung cancer as a cause of cancer-related death. This year 150,000 new cases of colorectal cancer will be diagnosed, and nearly 50,000 deaths will result from the disease in North America (http://seer.cancer.gov/cgi-bin/csr/). There is clearly an unmet need for new strategies to treat colon cancer. The proposed study focuses on a bile acid binding protein that is a potential target for chemoprevention in colon cancer. Bile acids were recognized as risk factors in colon cancer more than 30 years ago, but the role of bile acids in the etiology and progression of the disease remains unclear. This proposal focuses on ileal bile acid binding protein (IBABP), a14-kDa protein that binds to bile acids and is expressed in the cytoplasm of epithelial cells of the ileum. A higher molecular weight form of IBABP, called IBABP-Long (IBABP-L) has been identified. IBABP-L arises from an alternative transcription start site and encodes a form of IBABP with a 49-residue N-terminal extension. Most significantly, mRNA encoding IBABP-L is up-regulated in human colon cancers by 20- to 50-fold. The hypothesis of this study is that IBABP-L is involved in the onset and progression of colorectal cancer, and that this protein could be an important target for anti-tumor therapy.
The Aims of the study are to: 1) Express a recombinant form of IBABP-L and determine if it binds to bile acids, including ursodeoxycholic acid (UDCA), a non-natural bile acid with chemopreventative properties, and 2) Raise antibodies that distinguish IBABP-L and IBABP-S and use these to assess the expression of IBABP-L in human colon adenomas and colon tumors. ? ?
| Fang, Changming; Filipp, Fabian V; Smith, Jeffrey W (2012) Unusual binding of ursodeoxycholic acid to ileal bile acid binding protein: role in activation of FXR?. J Lipid Res 53:664-73 |
| Fang, Changming; Dean, Jarrod; Smith, Jeffrey W (2007) A novel variant of ileal bile acid binding protein is up-regulated through nuclear factor-kappaB activation in colorectal adenocarcinoma. Cancer Res 67:9039-46 |
