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

项目总结 结直肠癌(CRC)是美国第三大恶性肿瘤。今年超过15万人 将诊断出结直肠癌病例，超过5万人将死于这种疾病 (http://ser.cancer.gov/cgi-bin/csr/).)因此，对新的治疗方法的医学需求尚未得到满足。 和预防CRC。 胆汁酸在高脂肪饮食的个体中升高，被认为是高血压的危险因素。 30多年前患上结直肠癌。矛盾的是，熊去氧胆酸，一种不是天然的胆汁酸 人类，但来自熊，实际上已经显示出结直肠的化学预防特性 癌症。尽管天然胆汁酸和结直肠癌之间存在联系，以及不寻常的化学预防性药物 熊去氧胆酸(UDCA)的性质、胆汁酸与结直肠的机制联系 癌症的定义仍然很模糊。 拟议的研究重点是核受体成员法尼类X受体a(FXRa) 在肠道中表达的转录因子家族。这种受体被胆汁酸激活， 并调节涉及胆汁酸稳态和细胞分化的靶基因的表达。这个 本研究的主要假设是FXRa信号通路是化学预防的有效靶点。 结直肠癌。 我们发现，FXRa的减少促进了两个独立的小鼠模型的肿瘤形成 结直肠癌。此外，我们还发现回肠胆汁酸结合蛋白(IBABP)以正的方式工作。 具有FXR的反馈环，对于FXR活动是必要的，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形成络合物，然后刺激FXRa。总之，这些结果表明， 有两种方法可以针对FXR途径进行化学预防：直接作用于FXR或通过增加FXR 通过IBABP进行活动。 为了验证我们的假设，我们将回答以下问题：1)FXRa是否具有保护作用 肠道肿瘤的发生？2)FXRa疗法什么时候适合预防结直肠癌？3)可以小 FXRa的分子激动剂预防CRC？4)UDCA的化学预防特性是由于其 与IBABP结合并相应反式激活FXRa？5)是 IBABP与结直肠癌的发展及对UDCA的反应？这项研究的结果很可能是 为化学预防提供新的方法，并为识别反应亚群提供新的分析方法。

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.