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Role of thyroid hormone receptor mutants in hepatocellular carcinoma

甲状腺激素受体突变体在肝细胞癌中的作用

基本信息

批准号：
7392190
负责人：
Martin L. Privalsky
金额：
$ 17.85万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-12-11 至 2009-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7392190
关键词：
Acute Erythroblastic Leukemia Address Adult Alleles Animals Clinical Complement Conventional (Clear Cell) Renal Cell Carcinoma Cultured Cells Defect Development Disease Dominant-Negative Mutation Endocrine System Diseases Erythroid Frequencies Growth Hormone Receptor Test Hormones Human In Vitro Incidence Intervention Kidney Ligands Liver Liver neoplasms Malignant Neoplasms Molecular Molecular Biology Mus Mutant Strains Mice Mutate Mutation Neoplasms Physiology Play Prevalence Prevention Primary carcinoma of the liver cells Property Protein Isoforms Protocols documentation Rate Research Personnel Resistance Role Syndrome Testing Thyroid Gland Thyroid Hormone Receptor Thyroid Hormones Tissues Transgenes Transgenic Mice Transgenic Model Transgenic Organisms United States base improved in vivo inhibitor/antagonist interest mouse model mutant neoplastic novel programs receptor function research study transcription factor transgene expression tumor tumor progression tumorigenesis

项目摘要

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.

肝细胞癌 (HCC) 是全世界最常见和最致命的成人癌症之一，在美国的患病率不断增加。超过 70% 的人类肝癌表达突变甲状腺激素受体（TR）。野生型 TR 作为激素调节转录因子。我们建议确定与肝癌相关的 TR 突变在建立或这些肿瘤的进展。从体外表征来看，我们知道几乎所有 HCC 突变体测试的 TR 作为野生型 TR 功能的显性失活抑制剂，并且野生型 TR 发挥培养细胞中的生长抑制作用至少可以被某些突变 TR 消除肝癌。我们现在寻求直接检查这些 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 TRalphal 或 TRalphal 的转基因小鼠品系突变体首先从人类肝癌中分离出来。每个转基因将获得数名独立创始人等位基因并进行分析。转基因小鼠品系显示出与野生型和小鼠相似的表达水平 HCC 突变 TR 与未修饰的对照小鼠将用于特定目标 2。具体目标 2. 我们将分析未修饰和转基因品系的发病率、进展和类型瘤形成。我们特别感兴趣的是确定转基因菌株是否表现出改变的速率，与未修饰的小鼠相比，HCC 的进展或表现。我们将使用自发的和自发的化学诱导 HCC 方案，用于研究转基因作为引发剂和修饰剂的影响肿瘤计划。具体目标 3. 我们将把转基因研究扩展到与 HCC 相关的其他 TR 突变体，以及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频繁发生。我们的所提出的实验旨在提高我们对这一现象背后基础的理解，并且可能建议改进这些人类癌症的治疗。