RNA-binding protein HuR in liver pathophysiology and carcinogenesis

RNA结合蛋白HuR在肝脏病理生理学和癌发生中的作用

• 批准号: 10380114
• 负责人: Yuxia Zhang
• 金额: $ 36.04万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-03 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10380114
• 关键词: 3' Untranslated Regions; Adenine; Automobile Driving; Binding; Binding Sites; Cancer Etiology; Data; Development; Diethylnitrosamine; Down-Regulation; Elements; Embryo; Foundations; Functional disorder; Genes; Genetic Transcription; Goals; Growth; Health; Hepatic; Hepatocarcinogenesis; Hepatocyte; HuR protein; Human; In Vitro; Inflammation; Inflammatory; Intervention; Kansas; Knock-out; Knockout Mice; Lead; Link; Liver; Malignant Epithelial Cell; Malignant Neoplasms; Medical; Molecular; Mus; Nuclear Receptors; Oncogenic; Oncoproteins; Pathogenesis; Pathway interactions; Phosphorylation; Phosphorylation Site; Prevention; Primary Malignant Neoplasm of Liver; Primary carcinoma of the liver cells; Proteins; RNA-Binding Proteins; Regulation; Role; Signal Pathway; Signal Transduction; Survival Rate; Testing; Therapeutic; Tissues; Translations; Tumor Suppressor Proteins; Universities; Uridine; Xenograft procedure; cancer type; carcinogenesis; cell growth; chronic liver injury; clinically significant; exosome; hepatocellular carcinoma cell line; in vivo; inhibitor; insight; knockout gene; liver cancer model; liver inflammation; macrophage; mortality; mouse model; novel; novel strategies; p65; patient derived xenograft model; rab GTP-Binding Proteins; therapeutic target; transcriptome; transcriptome sequencing; tumor; tumor growth

PROJECT SUMMARY Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and has one of the worst 1- year survival rates of any cancer. There is a major need for understanding of the molecular mechanisms leading to HCC and developing novel strategies for effective prevention and treatment. HCC arises exclusively on the background of chronic liver injury and inflammation. Thus, targeting key genes that regulate both inflammation and oncogenic pathways in HCC appears to be an attractive therapeutic approach. RNA-binding protein Hu Antigen R (HuR) is one such candidate that controls the translation of multiple genes involved in inflammation and oncogenic signaling pathways through binding to the adenine- and uridine-rich elements located on 3'-untranslated region (UTR). Abnormal increase and cytoplasmic distribution of HuR has been linked to carcinogenesis in many types of cancers. However, little is known about the regulation and in vivo function of HuR in liver pathophysiology and carcinogenesis, largely due to the embryonic lethality of whole body HuR-null mice. Our previous studies have demonstrated that small heterodimer partner (Shp, Nr0b2), a nuclear receptor highly expressed in normal hepatocytes, is a tumor suppressor in HCC. We recently identified that HuR is activated in Shp-deficient hepatocytes and is transported to macrophages via exosomes, stimulating macrophage pro-inflammatory activation. The objective of this application is to characterize the role and molecular mechanism by which HuR regulates liver inflammation and hepatocarcinogenesis, and further test interventions to specifically target HuR for HCC prevention and treatment. Our central hypothesis is that the activation of HuR in hepatocytes promotes multiple oncogenic pathway activation as well as the exosome- stimulated liver inflammation that enhances liver carcinogenesis, while HuR inhibitor suppresses both liver inflammation and oncogenic pathways activation, leading to inhibition on HCC. In order to accomplish our goals, we propose the following specific aims: Aim 1. Characterize the molecular mechanisms that lead to HuR activation during hepatocarcinogenesis. Aim 2. Determine the function impact and downstream signaling of HuR in driving liver inflammation and carcinogenesis using hepatocyte-specific gene knockout mouse model. Aim 3. Evaluate the anti-tumor efficiency of a novel HuR inhibitor in HCC models. Our study will provide a foundation for understanding the role of HuR in liver pathophysiology and carcinogenesis. If the proposed aims are accomplished, the possibility of targeting HuR for HCC prevention and treatment will emerge, making this project of high clinical significance and translational value.

项目摘要 肝细胞癌（HCC）是世界上最常见的癌症之一，并且具有最严重的1- 任何癌症的年生存率。有一个主要的需要了解的分子机制 导致HCC和开发有效预防和治疗的新策略。HCC仅产生于 在慢性肝损伤和炎症的背景下。因此，靶向调节这两种基因的关键基因， 在HCC中的炎症和致癌途径似乎是一种有吸引力的治疗方法。rna结合 蛋白Hu抗原R（HuR）是这样一种候选物，其控制参与免疫应答的多个基因的翻译。 炎症和致癌信号通路通过结合腺嘌呤和尿苷丰富的元素 位于3 '-非翻译区（UTR）。HuR的异常增加和胞质分布已被证实是 与多种癌症的致癌作用有关。然而，关于调控和体内 HuR在肝脏病理生理学和癌变中的作用，主要是由于整个胚胎的致死性， 体HuR缺失小鼠。我们之前的研究已经证明小异二聚体伴侣（Shp，Nr 0 b2），一种 核受体在正常肝细胞中高度表达，是HCC中的肿瘤抑制因子。我们最近发现 HuR在缺乏Shp的肝细胞中被激活，并通过外泌体转运到巨噬细胞， 刺激巨噬细胞促炎活化。该应用程序的目的是描述角色 以及HuR调节肝脏炎症和肝癌发生的分子机制，并进一步 测试干预措施，专门针对HuR用于HCC预防和治疗。我们的核心假设是， 肝细胞中HuR的激活促进多种致癌途径的激活以及外泌体的激活， 刺激肝脏炎症，增强肝癌发生，而HuR抑制剂抑制两个肝脏 炎症和致癌途径激活，导致对HCC的抑制。为了实现我们的 为了实现这些目标，我们提出了以下具体目标：目标1。表征导致HuR的分子机制 在肝癌发生过程中激活。目标二。确定功能影响和下游信令 HuR在使用肝细胞特异性基因敲除小鼠模型驱动肝脏炎症和癌变中的作用。 目标3。评估新型HuR抑制剂在HCC模型中的抗肿瘤效率。我们的研究将提供一个 为理解HuR在肝脏病理生理学和癌变中的作用奠定了基础。如果提出的目标 一旦完成，靶向HuR用于HCC预防和治疗的可能性将出现， 具有很高的临床意义和转化价值。