NcoA5, a unique nuclear receptor coactivator in hepatocarcinogenesis

描述（由申请人提供）：男性肝细胞癌（HCC）的发病率是女性的2 - 4倍，男性慢性肝病进展为肝硬化的速度比女性快得多。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，更好地了解有助于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，预后或治疗靶点。长期目标是了解细胞中的遗传改变如何导致肝癌发生。本研究的目的是确定核受体辅激活因子5（Ncoa 5）下调促进HCC发生的机制。核心假设是Ncoa 5缺乏通过抑制雌激素受体1（ER？）活性和肝中雄激素受体（AR）表达的上调。这一假设是根据我们最近的初步数据提出的。这项研究的基本原理是，了解Ncoa 5介导的HCC抑制机制将揭示一种新的调控途径和新的靶点，用于开发预防和治疗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）。使用新的基因工程小鼠模型确定雌激素对Ncoa 5缺乏诱导的肝癌发生的影响;和2）确定Ncoa 5对枯否细胞和肝细胞发挥作用的分子机制。该方法是创新的，因为它利用了一种新的自发性HCC的基因工程小鼠模型来证明Ncoa 5在抑制HCC发展中的关键作用。这项研究意义重大，因为它有望证明Ncoa 5是一种新型的小鼠肿瘤抑制因子，具有与ER？和AR介导的HCC调节途径。这不仅将促进我们对肝癌病因机制的了解，而且还为基础和临床前研究领域提供了一种模拟人类肝癌发生和进展的新小鼠模型。 公共卫生相关性：这项研究与公共卫生有关，因为肝细胞癌（HCC）动物模型的建立和HCC性别差异机制的发现不仅有助于更全面地了解性激素在肝癌发生中的作用，而且还有助于发现新的病因，预后或治疗靶点。因此，拟议的研究与NIH的使命的一部分有关，即开发肝癌的预防和/或治疗。

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.