Interplay of bile acid and estrogen signaling

胆汁酸和雌激素信号的相互作用

• 批准号: 10321241
• 负责人: Ruitang Deng
• 金额: $ 33.5万
• 依托单位: UNIVERSITY OF RHODE ISLAND
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10321241
• 关键词: Agonist; Bile Acids; CCND1 gene; Cancer Etiology; Cessation of life; Chemicals; Cholestasis; Complex; Development; Elements; Estrogen Receptor Status; Estrogen Receptors; Estrogens; Exhibits; Functional disorder; Genetic Epistasis; Hepatic; In Vitro; Knock-out; Knockout Mice; Laboratories; Link; Liver diseases; MDM2 gene; Malignant Neoplasms; Malignant neoplasm of liver; Mediating; Molecular; Molecular Conformation; Mus; Nature; Oncogenes; Oncogenic; Pathogenesis; Patients; Peptide Hydrolases; Phenotype; Predisposition; Primary carcinoma of the liver cells; Protein Isoforms; Proteins; Receptor Activation; Receptor Signaling; Regulation; Resistance; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Testing; Transactivation; Ubiquitin; Variant; aged; antagonist; base; design; early phase clinical trial; effective therapy; experience; experimental study; in vivo; innovation; insight; novel; novel therapeutics; personalized medicine; promoter; receptor; receptor expression; recruit; therapy development; tumor

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.

肝细胞癌 (HCC) 是全球第六大常见癌症，也是导致癌症的第三大原因 与癌症相关的死亡。目前，治疗 HCC 患者的选择有限。迫切需要 开发针对 HCC 的有效疗法。法尼醇 X 受体 (FXR) 和雌激素受体 α (ERα) 信号传导 与 HCC 相关。大量证据支持 FXR 和 ERα 信号提供保护的观点 对抗HCC的发展。 FXR 基因敲除 (FXR-KO) 小鼠随着年龄的增长自发发展为 HCC ERα-KO 小鼠表现出对化学诱导的 HCC 的易感性增加。与其保护作用一致 在 HCC 中，很大比例 (60-80%) 的 HCC 患者中 FXR 和 ERα 信号传导失调或有缺陷 FXR 或 ERα 表达减少或完全缺乏，同时切换到其变体或不同的 同工型。在我们对 FXR-KO、ERα-KO 以及双 FXR 和 ERα 敲除 (FXR/ERα-DKO) 的初步研究中 在小鼠中，我们发现 FXR 和 ERα 信号通过协调调节一种新的机制相互串扰 癌基因泛素特异性肽酶 2 (USP2) 在 HCC 发展中的作用。本次活动的总体目标 该提案旨在了解 FXR 和 ERα 信号在 HCC 发展中的相互作用及其潜在机制 机制。基于我们广泛的初步结果的中心假设是 FXR 和 ERα 信号传导 具有肿瘤保护和促进活性，依赖于其他信号传导的状态 USP2以相互拮抗的方式进行调节。具体目标 1 是描述 FXR 和 HCC 发展中的 ERα 信号传导。具体目标 2 是确定 USP2 作为下游下游的致癌作用 FXR 和 ERα 信号在 HCC 发展中的靶标。具体目标 3 是研究其机制 深入了解 FXR 和 ERα 信号在调节 USP2 中有趣的串扰。该研究代表 描绘 HCC 中 FXR 和 ERα 信号传导复杂性和交互性质的开创性努力 发展。所提出的实验是建立在我们广泛、稳健和新颖的初步发现的基础上的： 以及我们在研究 FXR 和 ERα 信号传导及其在肝脏疾病中的相互作用方面的长期经验 包括胆汁淤积和肝癌。凭借新生成的 FXR/ERα-DKO 小鼠，我们的实验室具有独特的优势 准备研究 FXR 和 ERα 信号在 HCC 发展中的相互作用。落实这些 创新概念和发现有望极大地促进新疗法的开发 对于肝癌。