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.

项目总结