NcoA5, a unique nuclear receptor coactivator in hepatocarcinogenesis

描述（由申请人提供）：男性肝细胞癌（HCC）的发病率比女性高2 - 4倍，男性慢性肝病向肝硬化的进展比女性快得多。这些提示性激素在肝癌发生中起重要作用。然而，HCC中性别差异的分子机制仍然知之甚少。对于HCC患者使用激素治疗一直存在争议。因此，更好地了解导致HCC发展的遗传和表观遗传改变，特别是HCC的性别差异，可能会发现新的病因学、预后或治疗靶点。长期目标是了解细胞中的基因改变是如何导致肝癌发生的。本提案的目的是确定核受体共激活因子5 （Ncoa5）下调参与HCC发展的机制。核心假设是，Ncoa5缺乏通过抑制雌激素受体1 （ER?）活性和上调肝脏雄激素受体（AR）表达，优先促进男性肝癌的发生。这个假设是根据我们最近的初步数据提出的。本研究的基本原理是，了解ncoa5介导的HCC抑制机制将揭示新的调控途径和新的靶点，从而开发出预防和治疗HCC的创新策略。这一假设将通过以下两个具体目标进行检验：1)。用一种新的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作用的分子机制。该方法是创新的，因为它利用一种新型的自发性HCC基因工程小鼠模型来证明Ncoa5在抑制HCC发展中的关键作用。这项拟议的研究意义重大，因为它有望证明Ncoa5是一种新的小鼠肿瘤抑制因子，其单倍体功能不全与ER？以及AR介导的肝癌调控途径。这不仅将促进我们对HCC病因机制的理解，而且还将为基础和临床前研究领域提供一种新的模拟人类HCC发生和发展的小鼠模型。

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. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because the development of an animal model of hepatocellular carcinoma (HCC) and discovery of the mechanism underlying the gender disparity of HCC will not only contribute to a more comprehensive picture of the roles of sex hormone in Hepatocarcinogenesis, but also lead to the discovery of new etiologic, prognostic or therapeutic targets. Thus, the proposed research is relevant to the part of NIH's mission that pertains to developing the prevention and/or treatment of liver cancer.