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: 10601033
• 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 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10601033
• 关键词: 3' Untranslated Regions; Adenine; Automobile Driving; Binding; Binding Sites; Cancer Etiology; Cytoplasm; 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; Link; Liver; LoxP-flanked allele; Macrophage; 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 Promotion; Tumor Suppressor Proteins; Universities; Uridine; Xenograft procedure; cancer type; carcinogenesis; cell growth; chronic liver injury; clinical translation; clinically significant; exosome; hepatocellular carcinoma cell line; in vivo; inhibitor; insight; knockout gene; liver cancer model; liver inflammation; 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.

项目总结 肝细胞癌是世界上最常见的癌症之一，也是世界上最严重的癌症之一。 任何癌症的一年存活率。有一个主要的需要了解分子机制。 导致肝细胞癌，并开发有效预防和治疗的新策略。肝细胞癌完全发生在 在慢性肝损伤和炎症的背景下。因此，以调节两者的关键基因为靶点 肝细胞癌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)就是这样一个候选基因，它控制着多个基因的翻译 通过与富含腺嘌呤和尿苷的元件结合的炎症和致癌信号通路 位于3‘-非翻译区(UTR)。HUR的异常增加和胞浆分布 在许多类型的癌症中与致癌有关。然而，人们对这种调节和体内情况知之甚少。 HUR在肝脏病理生理和致癌中的作用，主要是由于整个胚胎的致死性 体色缺失的小鼠。我们以前的研究已经证明，小分子杂二聚体伙伴(SHP，Nr0b2)，a 核受体在正常肝细胞中高表达，是肝细胞癌的一种肿瘤抑制因子。我们最近确认了 HUR在SHP缺乏的肝细胞中被激活，并通过外切体运输到巨噬细胞， 刺激巨噬细胞的促炎活性。本应用程序的目标是描述角色的特征 和HUR调节肝脏炎症和肝癌发生的分子机制，并进一步 测试针对HUR的干预措施以预防和治疗肝细胞癌。我们的中心假设是 肝细胞内HUR的激活促进了多种致癌途径的激活，也促进了外切体的激活。 刺激的肝脏炎症增强了肝癌的发生，而HUR抑制剂抑制了两个肝脏 炎症和致癌途径被激活，导致对肝癌的抑制。为了完成我们的任务 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 肝细胞癌发生过程中的激活。目标2.确定功能影响和下游信号转导 利用肝细胞特异性基因敲除小鼠模型研究HUR在推动肝脏炎症和癌变中的作用。 目的3.评价一种新型Hur抑制剂在肝癌模型中的抗肿瘤作用。我们的研究将提供一个 为了解HUR在肝脏病理生理和致癌中的作用奠定基础。如果提议的目标是 一旦完成，靶向HUR用于肝癌预防和治疗的可能性将出现，使这 具有较高临床意义和翻译价值的项目。