Role of thyroid hormone receptor mutants in hepatocellular carcinoma

描述（由申请人提供）：肝细胞癌（HCC）是全球最常见和最致命的成人癌症之一，在美国的患病率正在增加。超过70%的人肝癌表达突变型甲状腺激素受体（TRs）。野生型TR作为转录因子调节的转录因子起作用。我们建议确定与肝癌相关的TR突变在这些瘤形成的建立或进展中的作用。从体外表征，我们知道，几乎所有的HCC突变TR测试的功能作为显性负抑制剂的野生型TR功能，和野生型TR发挥生长抑制作用，在培养的细胞中，被废除的至少某些突变TR在HCC中发现。我们现在试图在转基因模型中直接研究这些HCC TR突变体在体内肿瘤发生中的作用。具体目标1：我们将创建表达野生型TRP1或首先从人HCC分离的TRP1突变体的转基因小鼠系。对于每个转基因等位基因，将获得几个独立的建立者并进行分析。显示野生型和HCC突变TR的表达水平相当的转基因小鼠系以及未修饰的对照小鼠将用于特定目的2。具体目标2：我们将分析未修饰和转基因品系的肿瘤发生率、进展和类型。我们特别感兴趣的是，与未修饰的小鼠相比，转基因株是否显示出改变的HCC发生率、进展或表现。我们将使用自发和化学诱导的HCC方案来研究转基因作为肿瘤程序的引发剂和修饰剂的作用。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，并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。我们提出的实验旨在提高我们对这种现象背后的基础的理解，并可能建议改善这些人类癌症的治疗。

DESCRIPTION (provided by applicant): 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.