Nuclear envelope and predisposition to hepatic neoplasia

核膜和肝肿瘤易感性

• 批准号: 10720212
• 负责人: Ji-Yeon Shin
• 金额: $ 37.63万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10720212
• 关键词: Acceleration; Appearance; Automobile Driving; Binding; Carcinogens; Cell Culture Techniques; Cell Differentiation process; Cell Line; Cell Nucleus; Cell Proliferation; Cells; Chromatin; Chromatin Remodeling Factor; Cirrhosis; Data; Development; Disease; Gene Expression; Genes; Growth; Hepatic; Hepatocarcinogenesis; Hepatocyte; Homeostasis; Homologous Gene; Human; Injections; Iodothyronine Deiodinase; Lead; Ligands; Link; Lipids; Liver diseases; Liver neoplasms; Malignant Neoplasms; Membrane; Modeling; Mus; Mutation; Neoplasms; Nuclear; Nuclear Envelope; Nuclear Inner Membrane; Oncogenes; Oncogenic; Patients; Persons; Plasmids; Predisposition; Primary carcinoma of the liver cells; Process; Prognosis; Proliferating; Protein Isoforms; Proteins; Reporter; Research; Risk; Role; Testing; adeno-associated viral vector; alpha-Fetoproteins; cancer cell; chronic liver disease; env Gene Products; epigenetic regulation; fetal; genomic locus; hepatoma cell; high risk; imprint; in vivo; induced pluripotent stem cell; insight; lipid metabolism; liver cancer model; mouse model; neoplastic cell; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; notch protein; novel; polypeptide; prevent; progenitor; programs; selective expression; simple steatosis; stem cells; tumor; tumor initiation; tumor progression; tumorigenesis

PROJECT SUMMARY Chronic liver diseases such as nonalcoholic steatohepatitis significantly increase the risk of cirrhosis and hepatocellular carcinoma (HCC). However, the underlying mechanisms and genetic alterations that drive HCC development in chronic liver disease are poorly understood. There is therefore an urgent need to better understand the fundamental mechanisms how hepatocyte insults predispose to the development of HCC. This proposal investigates the novel mechanisms that can link alterations in the nuclear envelope to predisposition to HCC. Lamina-associated polypeptide 1 (LAP1) is an integral protein of the inner nuclear membrane that interacts with chromatin. We previously showed that depletion of LAP1 from hepatocytes alters hepatic lipid metabolism. Our new preliminary data demonstrate another unique role for LAP1 in predisposition to HCC. LAP1 undergoes an isoform switch during cell differentiation and a striking reversal in isoform expression occurs in mouse models of liver cancer as well as in human HCC. Furthermore, we have shown that depletion of LAP1 from mouse hepatocytes leads to spontaneous liver tumor formation and activation of fetal genes, including those within a specific genetic locus linked to tumorigenesis, prior to the appearance of tumors. These results have led us to hypothesize that LAP1 regulates hepatocyte differentiation and loss of expression of a long isoform and/or switching to the expression of a small isoform contributes to hepatic neoplasia. In Aim 1, we will test if LAP1 isoform change is a causal factor in driving hepatic neoplasia using diverse mouse models of hepatocarcinogenesis (Aim 1). We will also examine LAP1 expression in human HCC. In Aim 2, we will test the hypothesis that LAP1 isoforms have different effects on gene expression via epigenetic regulation by differential binding to chromatin or chromatin modifier proteins. We will use in vivo and cell culture models of HCC and examine hepatocyte differentiation of human induced pluripotent stem cells in which LAP1 isoforms are selectively expressed. The proposed research will uncover a new link between the nuclear envelope and hepatic neoplasia and provide insights into potential approaches to prevent or reverse HCC in the setting of chronic liver disease.

项目概要 慢性肝病，如非酒精性脂肪性肝炎，会显着增加肝硬化和肝硬化的风险。 肝细胞癌（HCC）。然而，驱动 HCC 的潜在机制和基因改变 人们对慢性肝病的发展知之甚少。因此迫切需要更好地 了解肝细胞损伤如何导致 HCC 发展的基本机制。这 该提案研究了将核膜的改变与易感性联系起来的新机制 肝癌。层相关多肽 1 (LAP1) 是内核膜的整合蛋白，与 与染色质。我们之前表明，肝细胞中 LAP1 的消耗会改变肝脏脂质代谢。 我们的新初步数据证明了 LAP1 在 HCC 易感性中的另一个独特作用。 LAP1 经历 细胞分化过程中的异构体转换以及小鼠模型中异构体表达的显着逆转 肝癌以及人类肝癌。此外，我们还发现小鼠中 LAP1 的缺失 肝细胞导致自发性肝肿瘤形成和胎儿基因的激活，包括胎儿基因内的基因 在肿瘤出现之前，与肿瘤发生相关的特定遗传位点。这些结果使我们 假设 LAP1 调节肝细胞分化和长异构体表达的丧失和/或 转而表达小亚型会导致肝肿瘤。在目标 1 中，我们将测试 LAP1 是否 使用不同的小鼠模型，亚型变化是驱动肝肿瘤形成的一个因果因素 肝癌发生（目标 1）。我们还将检查人类 HCC 中的 LAP1 表达。在目标 2 中，我们将测试 假设 LAP1 亚型通过差异表达的表观遗传调控对基因表达产生不同的影响 与染色质或染色质修饰蛋白结合。我们将使用 HCC 的体内和细胞培养模型 检查人诱导多能干细胞的肝细胞分化，其中 LAP1 亚型是 有选择地表达。拟议的研究将揭示核膜和肝脏之间的新联系 肿瘤形成并提供对慢性肝病中预防或逆转 HCC 的潜在方法的见解 疾病。