Sphinx: a new cause of hepatic neoplasia

描述(申请人提供)：肝细胞癌(HCC)占肝脏原发恶性肿瘤的85%，是世界上第三大与癌症相关的死亡原因。尽管其病因多种多样，但肝细胞癌的发展遵循一个共同的病因学特征，即反复肝损伤导致肝硬变、增生性结节的形成和遗传异常的积累。使用正向遗传方法，我们已经确定了一种由N-乙基-N-亚硝脲(ENU)诱导的种系突变表型，称为狮身人面像，它会发展为自发性多中心肝肿瘤。5周龄时肿瘤形成明显，组织学分析显示组织分化良好，未见肿瘤转移。除肝细胞肿瘤外，纯合子Sphinx小鼠还表现出淋巴细胞发育异常，缺乏外周血CD8+T细胞和NK细胞。表型表现为隐性性状，C57BL/6JSphinx/Sphinx小鼠12周龄死亡。粗略定位将突变定位在6号染色体上的一个小区间内，没有发现明显的候选基因。这项建议的目标是确定携带导致上述表型的突变的基因。此外，我们打算更详细地描述Sphinx的表型，并研究免疫系统和肿瘤细胞发育之间的相互作用。我们相信，我们的研究将揭示一个与肝癌发生有关的新基因，并为研究免疫系统与肝细胞肿瘤形成之间的相互作用提供一个新的、有用的模型系统。公共卫生相关性：这些研究的目的是确定一个未知的肿瘤抑制基因，涉及肝细胞腺瘤/癌的发展。此外，利用我们实验室确定的一种独特的小鼠模型，我们的目标是研究免疫系统在肝细胞肿瘤发展的病理生理学中的参与。

DESCRIPTION (provided by applicant): Hepatocellular carcinoma (HCC) accounts for 85% of primary malignant tumors of the liver and is the third most-common cause of cancer-related death in the world. Although its etiology is diverse, the development of HCC follows a common pathogenic profile with repetitive hepatic injury leading to cirrhosis, formation of hyperplastic nodules and accumulation of genetic aberrations. Using a forward genetic approach, we have identified an N-ethyl-N-nitrosourea (ENU)-induced germline mutant phenotype, called Sphinx that develops spontaneous multicentric liver tumors. Tumor formation is apparent by 5 weeks of age and histological analyses revealed that the tissue is well differentiated and no etastases were observed. In addition to hepatocellular tumor development, homozygous Sphinx mice exhibit abnormal lymphocyte development and lack peripheral CD8+ T and NK cells. The phenotypes behave as recessive traits and C57BL/6JSphinx/Sphinx mice die by 12 weeks of age. Coarse mapping placed the mutation in a small interval on chromosome 6, in which no obvious candidate genes were found. The goal of this proposal is to identify the gene carrying the mutation responsible for the described phenotypes. In addition, we intend to characterize the Sphinx phenotype in more detail and to study the interaction between the immune system and tumor cell development. We believe our studies will reveal a novel gene involved in HCC development and provide a new, useful, model system in which to study the interaction between the immune system and hepatocellular tumor formation. PUBLIC HEALTH RELEVANCE: The studies are aimed to identify a yet unknown tumor suppressor gene involved in hepatocellular adenoma/carcinoma development. In addition, using a unique mouse model identified in our laboratory, we aim to study the involvement of the immune system in the pathophysiology of hepatocellular tumor development.