Endocrine Regulation of Hepatocellular Carcinogenesis

描述(申请人提供)：肝细胞癌(肝细胞癌)主要是一种男性疾病；在过去的20年里，男性和女性的发病率都急剧上升。有证据表明，雌激素对肝癌有保护作用，而雄激素则促进肝癌的发生。用二乙基亚硝胺(DEN)处理的幼鼠作为研究这些荷尔蒙影响的模型。虽然肝脏表达雌激素受体(ERA)，但雌激素的保护作用可能是通过催乳素(PRL)介导的；目前尚不清楚是否需要肝脏ERA或PRL受体(PRLR)来发挥保护作用。目前也不清楚肝脏雄激素受体(AR)是否对男性肝癌的雄激素促进作用是必要的。长期目标是确定导致肝细胞癌性别差异的分子机制，并确定环境污染物是否影响这些机制。本探索性研究的目的是：1)确定肝脏激素受体在肝癌变过程中的调控作用。工作假说是Era和AR调节基因表达、细胞增殖和凋亡，从而分别抑制或促进肿瘤生长。这一假说将在肿瘤发生实验中用野生型和受体基因敲除小鼠进行验证。2)确定肝脏激素作用的分子机制。工作假说是雌激素保护和雄激素增强来自相反的基因调控事件。我们将确定在肝脏中由雌激素和雄激素相互调节的基因。致癌物引发的小鼠肝细胞癌具有与肝炎病毒和其他危险因素相关的进行性人类肝病的发病特征，最终导致肝细胞癌，因此，在小鼠中描述的疾病过程的激素调节机制将与人类的情况相关。这些研究还将为未来研究肝细胞癌发生中性别差异的内分泌干扰的可能性奠定基础。此外，识别出的基因产物可能会产生新的生物标记物，有助于预测接触内分泌干扰物化学品和其他对肝脏有有害影响的环境化学品。

DESCRIPTION (provided by applicant): Hepatocellular carcinoma (HCC) is mainly a male disease; incidence in both men and women has increased dramatically over the past 20 yrs. Evidence indicates that estrogens protect against HCC while androgens promote it. The infant mouse treated with diethylnitrosamine (DEN) serves as a model to study these hormonal influences. Although the liver expresses estrogen receptor (ERa), the protective effects of estrogen may be mediated through prolactin (PRL); whether liver ERa or PRL receptor (PRLR) is required for the protective effect is not known. It is also unknown if liver androgen receptor (AR) is essential for androgen promotion of HCC in males. The long term goals are to determine the molecular mechanisms accounting for gender differences in HCC and to determine if environmental contaminants impinge on those mechanisms. The aims of this exploratory investigation are: 1) Determine the role of hepatic hormone receptors in modulation of liver carcinogenesis. The working hypothesis is that ERa and AR regulate expression of genes, cell proliferation and apoptosis, thereby inhibiting or promoting, respectively, tumor growth. The hypothesis will be tested using wildtype and receptor knockout mice in tumorigenesis experiments. 2) Determine the molecular mechanisms of hormonal effects in the liver. The working hypothesis is that estrogen protection and androgen enhancement derive from opposing gene regulatory events. We will determine the genes that are reciprocally regulated in the liver by estrogen and androgen. Carcinogen-initiated HCC in the mouse shares features of pathogenesis with progressive human liver disease associated with hepatitis viruses and other risk factors that ultimately result in HCC and, therefore, mechanisms of hormonal modulation of the disease process delineated in the mouse will be relevant to the human situation. These studies will also lay the basis for future investigations into the potential for endocrine disruption of the gender differences in hepatocellular carcinogenesis. Furthermore, the gene products identified may yield new biomarkers useful in predicting exposure to endocrine disrupter chemicals and other environmental chemicals that have deleterious effects in the liver.