Role of thyroid hormone receptor mutants in hepatocellular carcinoma

肝细胞癌（HCC）是世界范围内最常见和最致命的成人癌症之一， 在美国的流行率正在上升。超过70%的人肝癌表达突变型甲状腺素 激素受体（TRs）。野生型TR作为转录因子调节的转录因子起作用。我们提出 确定与肝癌相关的TR突变在建立或 这些肿瘤的进展。从体外表征，我们知道几乎所有的HCC突变体， 测试的TR作为野生型TR功能的显性负抑制剂发挥功能，并且野生型TR发挥 在培养的细胞中的生长抑制作用，所述生长抑制作用被在以下中发现的至少某些突变TR消除： 肝癌我们现在试图直接研究这些HCC TR突变体在体内肿瘤发生中的作用， 转基因模型 具体目标1.我们将创建表达野生型TRP1或TRP1的转基因小鼠品系。 突变体首先从人HCC中分离。每个转基因将获得几个独立的创始人 等位基因并进行分析。转基因小鼠系显示野生型和野生型的表达水平相当， HCC突变TR与未修饰的对照小鼠一起将用于特定目的2。 具体目标2。我们将分析未修饰和转基因品系的发病率，进展和类型， 肿瘤形成我们特别感兴趣的是确定转基因菌株是否显示出改变的速率， 与未修饰的小鼠相比，HCC的进展或呈现。我们将同时使用一个自发的和一个 化学诱导的HCC方案，以研究转基因作为引发剂和修饰剂的作用 肿瘤治疗项目 具体目标3。我们将把我们的转基因研究扩展到与HCC相关的其他TR突变体， 将它们的作用与与其他肿瘤或内分泌疾病相关的TR突变体的作用进行比较。 相关性：甲状腺激素受体的改变在人类肝脏肿瘤中发生频率很高。我们 拟议的实验试图提高我们对这种现象背后的基础的理解，并可能 表明这些人类癌症的治疗有所改进。

Hepatocellular cancer (HCC) is among the most common and most lethal adult cancers worldwide, and is increasing in prevalence in the United States. Over 70% of human hepatocarcinomas express mutant thyroid hormone receptors (TRs). Wild-type TRs function as hormone-regulated transcription factors. We propose to determine the role of the TR mutations associated with hepatocarcinoma in the establishment or progression of these neoplasia. From characterizations in vitro, we know that virtually all of the HCC mutant TRs tested function as dominant-negative inhibitors of wild-type TR function, and that wild-type TRs exert growth suppressive effects in cultured cells that are abrogated by at least certain of the mutant TRs found in HCCs. We now seek to directly examine the role of these HCC TR mutants in oncogenesis in vivo in a transgenic model. Specific aim 1. We will create transgenic mouse lines expressing either wild-type TRalphal or a TRalphal mutant first isolated from a human HCC. Several independent founders will be obtained for each transgenic allele and analyzed. Transgenic mouse lines displaying comparable levels of expression of wild-type and HCC mutant TRs, together with unmodified control mice, will be employed for specific aim 2. Specific aim 2. We will analyze the unmodified and transgene lines for incidence, progression, and type of neoplasia. We are particularly interested in determining if the transgenic strains display altered rates, progression, or presentation of HCC compared to unmodified mice. We will use both a spontaneous and a chemically-induced HCC protocol to investigate the effects of the transgene as an initiator and as a modifier of the neoplastic program. Specific aim 3. We will expand our transgenic study to additional TR mutants associated with HCC, and compare their actions to those of TR mutants associated with other neoplastic or endocrine disorders. Relevance: Alterations in thyroid hormone receptors occur at high frequency in human liver tumors. Our proposed experiments seek to improve our understanding of the basis behind this phenomenon, and may suggest improvements in the treatment of these human cancers.