Interplay of bile acid and estrogen signaling

肝细胞癌（HCC）是世界范围内第六大常见癌症，也是肝细胞癌的第三大病因。 与癌症有关的死亡目前，治疗HCC患者的选择有限。迫切需要 为HCC开发有效的治疗方法。法尼醇X受体（FXR）和雌激素受体β（ER β）信号传导 与HCC有关。大量证据支持FXR和ER β信号提供保护的观点， 发展HCC。FXR敲除（FXR-KO）小鼠随着年龄的增长自发地发展为HCC， ER基因敲除小鼠表现出对化学诱导的HCC的易感性增加。与它们的保护作用一致 在HCC中，FXR和ER β信号在大部分HCC患者中（60-80%）失调或缺陷 FXR或ER β表达减少或完全缺乏，同时转换为其变体或不同的 同种型。在我们对FXR-KO、ER β-KO和FXR和ER β双敲除（FXR/ER β-DKO）的初步研究中， 在小鼠中，我们发现FXR和ER β信号通过协调调节一种新的 癌基因泛素特异性肽酶2（USP 2）在HCC发生发展中的作用。本报告的总体目标 我们的建议是了解FXR和ER β信号在HCC发展中的相互作用， 机制等基于我们广泛的初步结果，中心假设是FXR和ER信号转导 具有肿瘤保护和促进活性，这取决于其他信号传导的状态， 以相互拮抗的方式调节USP 2。具体目标1是描述FXR和 肝癌发展中的ER β信号转导。具体目标2是确定USP 2作为下游肿瘤抑制剂的致癌作用。 FXR和ER β信号通路在HCC发展中的作用靶点。具体目标3是研究 深入了解FXR和ER β信号在调节USP 2中的有趣串扰。该研究代表了 这是一项开创性的工作，旨在阐明HCC中FXR和ER β信号传导的复杂性和相互作用的性质， 发展提出的实验是建立在我们广泛的，强大的和新颖的初步发现， 以及我们在研究FXR和ER β信号传导及其在肝脏疾病中相互作用方面的长期经验 包括胆汁淤积和肝细胞癌通过新产生的FXR/ER β-DKO小鼠，我们的实验室因此是独一无二的。 准备研究FXR和ER β信号在HCC发展中的相互作用。执行这些 创新概念和发现预计将极大地推动新型疗法的开发 对于HCC。

Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the third leading cause of cancer-related deaths. At present, there are limited options in treating HCC patients. There are urgent needs to develop effective therapies for HCC. Both farnesoid x receptor (FXR) and estrogen receptor  (ER) signaling are linked to HCC. A large body of evidence support a view that FXR and ER signaling provide protection against HCC development. FXR knockout (FXR-KO) mice spontaneously developed HCC as they aged while ER-KO mice exhibited increased susceptibility to chemical-induced HCC. Consistent with their protective roles in HCC, FXR and ER signaling were dysregulated or defective in large percentages (60-80%) of HCC patients with decreased or total lack of FXR or ER expression with concurrent switches to its variants or different isoforms. In our preliminary studies with FXR-KO, ER-KO and double FXR and ER knockout (FXR/ER-DKO) mice, we discovered that FXR and ER signaling crosstalked each other through coordinately regulating a novel oncogene ubiquitin specific peptidase 2 (USP2) in the development of HCC. The overall objective of this proposal is to understand the interplay of FXR and ER signaling in HCC development and the underlying mechanisms. The central hypothesis, built on our extensive preliminary results, is that FXR and ER signaling have both tumor-protective and promoting activities dependent on the status of the other signaling through their regulation of USP2 in a reciprocal antagonistic manner. Specific Aim 1 is to delineate the interplay of FXR and ER signaling in HCC development. Specific Aim 2 is to determine the oncogenic roles of USP2 as a downstream target of FXR and ER signaling in the development of HCC. Specific Aim 3 is to investigate the mechanistic insights into the intriguing crosstalk between FXR and ER signaling in regulating USP2. The study represents a pioneering effort to delineate the complex and interactive nature of FXR and ER signaling in HCC development. The experiments proposed are built on our extensive, robust and novel preliminary findings as well as our long-standing experience in studying FXR and ER signaling and their interaction in liver diseases including cholestasis and HCC. With newly generated FXR/ER-DKO mice, our laboratory is thus uniquely poised to investigate the interplay of FXR and ER signaling in HCC development. Implementation of these innovative concepts and findings is expected to greatly enable the advancement of developing novel therapies for HCC.