Isolation of a Human 11p11.2 Liver Tumor Suppressor Gene

人 11p11.2 肝肿瘤抑制基因的分离

• 批准号: 6720877
• 负责人: WILLIAM B COLEMAN
• 金额: $ 25.55万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6720877
• 关键词: carcinogenesis; cell line; clinical research; gene expression; gene induction /repression; gene mutation; genetic mapping; genetic screening; hepatoblastoma; hepatocellular carcinoma; human genetic material tag; human tissue; laboratory rat; laser capture microdissection; loss of heterozygosity; molecular oncology; neoplasm /cancer genetics; tissue /cell culture; transfection; tumor suppressor genes

DESCRIPTION (provided by applicant): Numerous studies suggest that inactivation of one or more tumor suppressor genes may represent early and/or necessary steps in the neoplastic transformation of liver. Human chromosome 11 has been implicated in the pathogenesis of several human tumors, including hepatoblastoma and hepatocellular carcinoma, and is syntenic to rat chromosome 1, which is structurally altered in many rat liver tumor cell lines, suggesting that these chromosomes may contain a common liver tumor suppressor gene. We have suggested that chromosome tranfer studies utilizing human chromsomes and rat liver tumor cell lines may facilitate the facile localization, identification, and cloning of human genes responsible for tumor suppression in liver. To this end, we have employed a microcell hybrid model to demonstrate the existence of a liver tumor suppressor on human chromosome 11, map its location to 11p11.2, and identify candidate ESTs/genes. The continuing long-term goal of this research project is to determine the role of the human 11p11.2 liver tumor suppressor gene in the molecular pathogenesis of hepatocellular carcinoma, and to determine the mechanisms that govern the loss of function of this tumor suppressor in multi-step hepatocarcinogenesis in humans. The proposed investigations focus on a small group of candidate liver tumor suppressor genes that were identified during the initial funding period, and extend/advance our ongoing studies aimed at characterizing these candidate genes. The goals of this proposal are to (i) characterize the involvement of candidate liver tumor suppressor genes in the suppression of the neoplastic phenotype of rat liver tumor cell lines using siRNA in vitro and in vivo, (ii) determine the ability of candidate genes to express tumor suppressor activity in vivo using transfected cell lines, (iii) evaluate the possible contributions of epigenetic mechanisms to the regulation of candidate liver tumor suppressor gene expression, (iv) examine the role of genetic alterations (LOH and/or mutation) in the inactivation of candidate liver tumor suppressor gene expression, (v) determine if alterations in candidate liver tumor suppressor gene expression represent early or later molecular alterations in multi-step hepatocarcinogenesis, and (vi) identify molecular targets and pathways in liver tumor cell lines that are subject to direct or indirect modification in response to candidate gene expression.

描述（由申请人提供）：大量研究表明，一种或多种肿瘤抑制基因的失活可能代表肝脏肿瘤转化中的早期和/或必要步骤。人类 11 号染色体与多种人类肿瘤（包括肝母细胞瘤和肝细胞癌）的发病机制有关，并且与大鼠 1 号染色体同线，后者在许多大鼠肝肿瘤细胞系中发生结构改变，表明这些染色体可能包含共同的肝肿瘤抑制基因。我们建议利用人类染色体和大鼠肝肿瘤细胞系进行染色体转移研究可能有助于轻松定位、鉴定和克隆负责肝脏肿瘤抑制的人类基因。为此，我们采用微细胞混合模型来证明人类 11 号染色体上存在肝脏肿瘤抑制因子，将其位置映射到 11p11.2，并鉴定候选 EST/基因。该研究项目的长期目标是确定人类 11p11.2 肝脏肿瘤抑制基因在肝细胞癌分子发病机制中的作用，并确定在多种疾病中控制该肿瘤抑制基因功能丧失的机制。人类肝癌的一步发生。拟议的研究重点是在最初资助期间确定的一小群候选肝脏肿瘤抑制基因，并扩展/推进我们正在进行的旨在表征这些候选基因的研究。本提案的目标是 (i) 表征候选肝肿瘤抑制基因在体外和体内使用 siRNA 抑制大鼠肝肿瘤细胞系肿瘤表型的作用，(ii) 确定候选基因抑制大鼠肝肿瘤细胞系肿瘤表型的能力使用转染的细胞系在体内表达肿瘤抑制活性，（iii）评估表观遗传机制对候选肝脏肿瘤抑制基因表达调节的可能贡献，（iv）检查遗传改变（LOH和/或突变）在肝脏肿瘤抑制基因表达中的作用。失活候选肝肿瘤抑制基因表达的变化，（v）确定候选肝肿瘤抑制基因表达的改变是否代表多步骤肝癌发生中的早期或晚期分子改变，以及（vi）鉴定受试肝肿瘤细胞系中的分子靶标和途径响应候选基因表达的直接或间接修饰。