FXR signaling pathway is a valid target for chemoprevention in colorectal cancer

项目摘要 结直肠癌（CRC）是美国第三大恶性肿瘤。今年超过15万 结直肠癌病例将被诊断出来，超过50，000人将死于这种疾病 (http：//ser.cancer.gov/cgi-bin/csr/）。因此，存在对用于治疗癌症的新方法的未满足的医学需求。 预防CRC。 高脂饮食者胆汁酸升高，被认为是 结直肠癌30多年前特别是，熊去氧胆酸，一种胆汁酸， 人类，但来自熊，实际上已经显示出结肠直肠癌的化学预防特性， 癌尽管天然胆汁酸和结直肠癌之间存在联系， 熊去氧胆酸（UDCA）的性质，胆汁酸与结直肠癌之间的机制联系， 癌症的定义仍然不明确。 这项研究的重点是法尼醇X受体a（FXRa），它是核受体的一员。 在肠道中表达的转录因子家族。这种受体被胆汁酸激活， 并调节参与胆汁酸稳态和细胞分化的靶基因的表达。的 这项研究的主要假设是，FXRa信号通路是化学预防的有效靶点， 结肠直肠癌 我们已经发现，在两个独立的小鼠模型中，FXRa的减少促进肿瘤发生。 结肠直肠癌此外，我们还发现回肠胆汁酸结合蛋白（IBABP）在一个阳性反应中起作用。 与FXR的反馈回路，是FXR活性所必需的，因此影响IBABP的因素可能会改变 FXR的功能，从而影响肿瘤的发病率和生长。我们还有证据表明 UDCA与IBABP形成复合物，然后刺激FXRa。这些结果表明， 靶向FXR通路进行化学预防有两种途径：直接打击FXR或通过增加FXR 通过IBABP。 为了验证我们的假设，我们将解决以下问题：1）FXRa是否具有保护 肠道肿瘤的发生2)FXRa治疗何时适合预防CRC？3)可小 FXRa分子激动剂预防CRC？4)UDCA的化学预防特性是否是其 结合IBABP和相应的反式激活FXRa？5)是单核苷酸多态性 IBABP与CRC的发生和UDCA的反应相关？这项研究的结果可能是 提供化学预防的新方法和鉴定应答亚群的新测定。

PROJECT SUMMARY Colorectal cancer (CRC) is the third-leading malignancy in the United States. This year more than 150,000 cases of colorectal cancer will be diagnosed and more than 50,000 people will die from the disease (http://ser.cancer.gov/cgi-bin/csr/). Consequently there is an unmet medical need for new methods for treating and preventing CRC. Bile acids, which are elevated in individuals with high fat diets, were recognized as risk factors for colorectal cancer more than 30 years ago. Paradoxically, ursodeoxycholic acid, a bile acid that is not natural to humans but which is derived from the bear, has actually shown chemopreventative properties for colorectal cancer. Despite the link between natural bile acids and colorectal cancer, and the unusual chemopreventative properties of ursodeoxycholic acid (UDCA), the mechanistic connections between bile acids and colorectal cancer remain poorly defined. The proposed study focuses on the farnesoid X receptor a (FXRa), a member of the nuclear receptor family of transcription factors that is expressed in the intestinal tract. This receptor is activated by bile acids, and regulates the expression of target genes involved in bile acid homeostasis and cell differentiation. The primary hypothesis of this study is that the FXRa signaling pathway is a valid target for chemoprevention in colorectal cancer. We have found that reduction of FXRa promotes tumorigenesis in a two independent mouse models of colorectal cancer. Moreover, we have found that ileal bile acid binding protein (IBABP) operates in a positive feedback loop with FXR and is necessary for FXR activity, thus factors that influence IBABP are likely to alter the function of FXR and therefore impact tumor incidence and growth. We also have evidence indicating that UDCA forms a complex with IBABP, which then stimulates FXRa. Together these results suggest that there are two routes to targeting the FXR pathway for chemoprevention: hitting FXR directly or by increasing FXR activity through IBABP. To test our hypothesis, we will address the following questions: 1) Does FXRa have a role in protecting the intestine from tumorigenesis? 2) When is FXRa therapy suitable for prevention of CRC? 3) Can small molecule agonists of FXRa prevent CRC? 4) Are the chemopreventative properties of UDCA a result of its binding to IBABP and the corresponding transactivation of FXRa? 5) Is the single nucleotide polymorphism of IBABP associated with the development of CRC and the response to UDCA? Results from this study are likely to provide new methods for chemoprevention, and novel assays for identifying responsive sub-populations.