NcoA5, a unique nuclear receptor coactivator in hepatocarcinogenesis

NcoA5，肝癌发生中独特的核受体共激活剂

• 批准号: 8328939
• 负责人: HUA XIAO
• 金额: $ 15.64万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-06 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8328939
• 关键词: AF2; Age; Alleles; Androgen Receptor; Androgens; Basic Science; Cells; Cirrhosis; Data; Development; Diethylnitrosamine; Down-Regulation; Epigenetic Process; Estrogen Receptor 1; Estrogen Receptors; Estrogens; Female; Future; Gender; Genes; Genetic; Genetically Engineered Mouse; Goals; Gonadal Steroid Hormones; Hepatocarcinogenesis; Hepatocyte; Human; Incidence; Interleukin-6; Knockout Mice; Kupffer Cells; Lead; Lesion; Link; Liver; Liver neoplasms; Malignant neoplasm of liver; Mediating; Messenger RNA; Mission; Molecular; Mus; Mutation; Nuclear Receptors; Outcome; Pathogenesis; Pathway interactions; Patients; Play; Prevention; Primary carcinoma of the liver cells; Principal Investigator; Process; Proteins; Public Health; Regulatory Pathway; Research; Rodent Model; Role; Specimen; Testing; Time; Tissues; Tumor Suppressor Proteins; Up-Regulation; Woman; Work; animal model development; base; chemical carcinogen; chronic liver disease; hormone therapy; innovation; male; men; mouse model; novel; pre-clinical research; preclinical study; prognostic; programs; receptor expression; research study; therapeutic target; tumor

DESCRIPTION (provided by applicant): The incidence of hepatocellular carcinoma (HCC) is two to four times higher in men than in women and the progression of chronic liver diseases to cirrhosis is much faster in men than in women. These suggest an important role of sex hormones in hepatocarcinogenesis. However, the molecular mechanism underlying the gender disparity in HCC still remains poorly understood. And there have been controversies on the use of hormonal therapies for patients with HCC. Hence, a better understanding of the genetic and epigenetic alterations that contribute to HCC development, especially to the gender disparity of HCC, may lead to a discovery of new etiologic, prognostic or therapeutic targets. The long- term goal is to understand how the genetic alterations in cells lead to hepatocarcinogenesis. The objective of this proposal is to determine the mechanism by which down regulation of nuclear receptor coactivator 5 (Ncoa5) contributes to the development of HCC. The central hypothesis is that Ncoa5 deficiency preferentially promotes hepatocarcinogenesis in males through inhibition of estrogen receptor 1 (ER?) activity and upregulation of androgen receptor (AR) expression in the liver. This hypothesis has been formulated on the basis of our recent preliminary data. The rationale for the proposed research is that understanding of the mechanism underlying Ncoa5-mediated suppression of HCC will reveal a novel regulatory pathway and new targets for developing innovative strategies to the prevention and treatment of HCC. This hypothesis will be tested by the following two specific aims: 1). Determine the effects of estrogen on Ncoa5 deficiency induced hepatocarcinogenesis using a novel genetically-engineered mouse model; and 2) Determine the molecular mechanism by which Ncoa5 exerts its effect on Kupffer cells and hepatocytes. The approach is innovative, because it utilizes a novel genetically-engineered mouse model of spontaneous HCC to prove a critical role of Ncoa5 in the suppression of HCC development. The proposed research is significant, because it is expected to demonstrate Ncoa5 as a novel mouse tumor suppressor with haploinsufficiency that links up ER? and AR mediated regulatory pathways to HCC. This will not only advance our understanding of the etiological mechanisms of HCC, but also provide the fields of basic and preclinical studies with a new mouse model that mimics the initiation and progression of human HCC.

描述（由申请人提供）：男性肝细胞癌（HCC）的发病率是女性的两到四倍，并且男性慢性肝病进展为肝硬化的速度比女性快得多。这些表明性激素在肝癌发生中发挥重要作用。然而，肝癌性别差异背后的分子机制仍然知之甚少。对于 HCC 患者使用激素疗法也存在争议。因此，更好地了解导致 HCC 发展的遗传和表观遗传改变，尤其是 HCC 的性别差异，可能会发现新的病因、预后或治疗靶点。长期目标是了解细胞的遗传改变如何导致肝癌发生。该提案的目的是确定核受体辅激活因子 5 (Ncoa5) 下调导致 HCC 发展的机制。核心假设是，Ncoa5 缺乏通过抑制肝脏中雌激素受体 1 (ER?) 活性和上调雄激素受体 (AR) 表达，优先促进男性肝癌发生。这一假设是根据我们最近的初步数据提出的。拟议研究的基本原理是，了解 Ncoa5 介导的 HCC 抑制机制将揭示新的调控途径和开发预防和治疗 HCC 创新策略的新目标。该假设将通过以下两个具体目标进行检验：1）。使用新型基因工程小鼠模型确定雌激素对 Ncoa5 缺乏诱导的肝癌发生的影响； 2)确定Ncoa5对库普弗细胞和肝细胞发挥作用的分子机制。该方法具有创新性，因为它利用新型基因工程小鼠自发性 HCC 模型来证明 Ncoa5 在抑制 HCC 发展中的关键作用。拟议的研究意义重大，因为它有望证明 Ncoa5 作为一种新型小鼠肿瘤抑制因子，其单倍体不足可连接 ER？ AR介导的HCC调节途径。这不仅将增进我们对 HCC 病因学机制的理解，而且还为基础和临床前研究领域提供一种模拟人类 HCC 发生和进展的新小鼠模型。