NcoA5, a unique nuclear receptor coactivator in hepatocarcinogenesis

描述(申请人提供)：男性的肝细胞癌发病率是女性的两到四倍，慢性肝病发展为肝硬变的男性比女性快得多。这些都表明性激素在肝癌的发生中起着重要作用。然而，肝癌性别差异背后的分子机制仍然知之甚少。对于肝细胞癌患者是否使用激素治疗也存在争议。因此，更好地了解有助于肝癌发生的遗传和表观遗传学改变，特别是导致肝癌的性别差异，可能会导致发现新的病因学、预后或治疗靶点。长期目标是了解细胞中的基因改变如何导致肝癌的发生。本研究的目的是确定核受体辅活化子5(NCOA5)下调在肝细胞癌发生中的作用机制。中心假说是NCOA5缺乏通过抑制雌激素受体1(ER？)优先促进男性肝癌的发生。肝脏雄激素受体(AR)表达的活性和上调。这一假设是根据我们最近的初步数据提出的。这项研究的理论基础是，了解NCOA5介导的抑制肝癌的机制将揭示一种新的调控途径和新的靶点，以开发预防和治疗肝癌的创新策略。这一假设将通过以下两个具体目标进行检验：1)。使用一种新的基因工程小鼠模型，确定雌激素在NCOA5缺乏诱导的肝癌发生中的作用；以及2)确定NCOA5对Kupffer细胞和肝细胞发挥作用的分子机制。这种方法是创新的，因为它利用了一种新的自发性肝癌基因工程小鼠模型来证明NCOA5在抑制肝癌发展中的关键作用。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，具有连接ER？AR介导了肝细胞癌的调控途径。这不仅将促进我们对肝细胞癌发病机制的认识，而且将为基础和临床前研究领域提供一种新的模拟人类肝细胞癌发生和发展的小鼠模型。 公共卫生相关性：拟议的研究与公共健康相关，因为建立肝细胞癌动物模型和发现肝癌性别差异的机制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任务中与开发肝癌预防和/或治疗相关的部分相关。

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.