Interplay of bile acid and estrogen signaling

胆汁酸和雌激素信号的相互作用

• 批准号: 10524236
• 负责人: Ruitang Deng
• 金额: $ 7.94万
• 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/10524236
• 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.

肝细胞癌是世界范围内第六大常见癌症和第三大致癌原因。 与癌症相关的死亡。目前，治疗肝细胞癌患者的选择有限。有迫切的需要 开发治疗肝细胞癌的有效方法。法尼醇X受体和雌激素受体(ER)的信号转导 与肝细胞癌有关。大量证据支持FXR和ER信号提供保护的观点 不利于肝癌的发展。FXR基因敲除(FXR-KO)小鼠随着年龄的增长自发地患上肝癌 ER-KO小鼠对化学诱导的肝癌的易感性增加。与他们的保护角色一致 在肝细胞癌中，FXR和ER信号在很大比例(60%-80%)的肝细胞癌患者中是异常或缺陷的 减少或完全缺乏FXR或ER表达，同时切换到其变体或不同 异构体。在我们对FXR-KO、ER-KO和双FXR和ER基因敲除(FXR/ER-DKO)的初步研究中 小鼠，我们发现FXR和ER信号通过协调调节一个新的 癌基因泛素特异肽酶2(USP2)在肝癌发生发展中的作用这样做的总体目标是 建议了解FXR和ER信号在肝癌发生发展中的相互作用及其潜在的 机制。建立在我们广泛的初步结果基础上的中心假设是，FXR和ER信号 是否肿瘤保护和促进活动都依赖于其他信号的状态 以相互拮抗的方式调节USP2。具体目标1是描绘FXR和 ER-信号在肝细胞癌发生发展中的作用具体目标2是确定USP2作为下游的致癌作用。 肝细胞癌发生发展中FXR和ER信号转导的靶点具体目标3是研究 对FXR和ER信号在调节USP2过程中的有趣串扰的洞察。这项研究代表了 描述肝细胞癌中FXR和ER信号的复杂和相互作用的开创性努力 发展。建议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，如 以及我们在肝脏疾病中研究FXR和ER信号及其相互作用的长期经验 包括胆汁淤积症和肝细胞癌。对于新生的FXR/ER-Dko小鼠，我们的实验室因此是独一无二的 准备研究FXR和ER信号在肝癌发生中的相互作用。这些措施的实施 创新的概念和发现有望极大地推动新疗法的发展 肝细胞癌的。

项目成果

Dysregulation and oncogenic activities of ubiquitin specific peptidase 2a in the pathogenesis of hepatocellular carcinoma.

泛素特异性肽酶 2a 在肝细胞癌发病机制中的失调和致癌活性。

• 发表时间: 2023
• 期刊: American journal of cancer research
• 影响因子: 5.3
• 作者: Zhang,Xinmu;Nadolny,Christina;Chen,Qiwen;Ali,Winifer;Hashmi,SyedF;Deng,Ruitang
• 通讯作者: Deng,Ruitang