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

描述（由申请人提供）：结直肠癌（CRC）是美国第三大恶性肿瘤。今年将有超过15万例结直肠癌被诊断出来，超过5万人将死于这种疾病（http://ser.cancer.gov/cgi-bin/csr/）。因此，对治疗和预防结直肠癌的新方法的医学需求尚未得到满足。胆汁酸在高脂肪饮食的个体中升高，30多年前就被认为是结直肠癌的危险因素。矛盾的是，熊去氧胆酸，一种非人类天然的胆汁酸，从熊身上提取出来，实际上显示出对结直肠癌的化学预防作用。尽管天然胆汁酸与结直肠癌之间存在联系，并且熊去氧胆酸（UDCA）具有不同寻常的化学预防特性，但胆汁酸与结直肠癌之间的机制联系仍不明确。拟研究的重点是farnesoid X受体a (FXRa)，它是在肠道中表达的转录因子核受体家族的成员。该受体被胆汁酸激活，调控胆汁酸稳态和细胞分化相关靶基因的表达。本研究的主要假设是FXRa信号通路是结直肠癌化学预防的有效靶点。我们发现，在两种独立的结直肠癌小鼠模型中，FXRa的减少促进了肿瘤的发生。此外，我们发现回肠胆汁酸结合蛋白（IBABP）与FXR呈正反馈回路，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，从而影响肿瘤的发生和生长。我们也有证据表明UDCA与IBABP形成复合物，然后刺激FXRa。总之，这些结果表明，有两种途径可以靶向FXR途径进行化学预防：直接击中FXR或通过IBABP增加FXR活性。为了验证我们的假设，我们将解决以下问题：1)FXRa是否在保护肠道免受肿瘤发生方面发挥作用？2) FXRa治疗何时适合预防结直肠癌？3) FXRa小分子激动剂能否预防结直肠癌？4) UDCA的化学预防特性是其与IBABP结合以及相应的FXRa转激活的结果吗？5) IBABP的单核苷酸多态性是否与CRC的发展和UDCA的反应有关？这项研究的结果可能为化学预防提供新的方法，并为识别反应性亚群提供新的检测方法。公共卫生相关性：尽管天然胆汁酸与结直肠癌之间存在联系，并且熊去氧胆酸（UDCA）具有不同寻常的化学预防特性，但胆汁酸与结直肠癌之间的机制联系仍不明确。拟研究的重点是farnesoid X receptor a (FXRa)，它是核受体转录因子家族中的一员，几乎只在肠道中表达，被胆汁酸激活，调控胆汁酸稳态相关靶基因的表达，在结直肠癌中下调。主要假设是FXRa信号通路是结直肠癌化学预防的有效靶点。这项研究的结果可能为化学预防提供新的方法，并为识别反应性亚群提供新的检测方法。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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 almost exclusively in intestinal tract, is activated by bile acids, regulates the expression of target genes involved in bile acid homeostasis, and is down-regulated in colorectal cancer. The primary hypothesis is that the FXRa signaling pathway is a valid target for chemoprevention in colorectal cancer. Results from this study are likely to provide new methods for chemoprevention, and novel assays for identifying responsive sub-populations.