A Variant of Ileal Bile Acid Binding Protein in Colon Cancer

描述(申请人提供)：结肠腺癌是美国第三大恶性肿瘤，在与癌症相关的死亡原因中仅次于肺癌。今年将诊断出150,000例新的结直肠癌病例，北美将有近50,000人死于这种疾病(http://seer.cancer.gov/cgi-bin/csr/).显然，对治疗结肠癌的新策略的需求尚未得到满足。这项拟议的研究重点是一种胆汁酸结合蛋白，它是结肠癌化学预防的潜在靶点。胆汁酸在30多年前就被认为是结肠癌的危险因素，但胆汁酸在疾病的病因和进展中的作用尚不清楚。这项建议的重点是回肠胆汁酸结合蛋白(IBABP)，一种14 kDa的蛋白，与胆汁酸结合，在回肠上皮细胞的细胞质中表达。现已鉴定出一种相对分子质量较高的IBABP-Long(IBABP-L)。IBABP-L来自另一个转录起始点，编码一种含有49个残基的N-末端延伸的IBABP。最重要的是，编码IBABBP-L的基因在人类结肠癌中上调了20-50倍。本研究的假设是IBABBP-L参与了结直肠癌的发生发展，该蛋白可能是抗肿瘤治疗的重要靶点。本研究的目的是：1)表达重组形式的IBBP-L并确定其是否与包括熊去氧胆酸在内的胆汁酸结合，熊去氧胆酸是一种具有化学预防作用的非天然胆汁酸；2)制备区分IBBP-L和IBBP-S的抗体，并用这些抗体来评估IBBP-L在结肠腺瘤和结肠癌中的表达。

DESCRIPTION (provided by applicant): 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.