Nuclear envelope and predisposition to hepatic neoplasia

项目摘要 慢性肝病如非酒精性脂肪性肝炎显著增加肝硬化的风险， 肝细胞癌（HCC）。然而，驱动HCC的潜在机制和遗传改变 慢性肝病的发展知之甚少。因此，迫切需要改善 了解肝细胞损伤如何诱发HCC发展的基本机制。这 这项提案研究了将核被膜的改变与易感性联系起来的新机制， HCC。核纤层相关多肽1（Lamina-associated polypeptide 1，LAP 1）是核内膜的一种整合蛋白， 染色质。我们以前发现，从肝细胞中消耗LAP 1会改变肝脏脂质代谢。 我们新的初步数据表明，LAP 1在HCC易感性中的另一个独特作用。LAP 1经历 在小鼠模型中，在细胞分化过程中发生同种型转换， 在肝癌和人肝癌中也是如此。此外，我们已经表明，小鼠LAP 1的缺失 肝细胞导致自发的肝肿瘤形成和胎儿基因的激活，包括那些在肝细胞内的基因。 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LAP 1调节肝细胞分化和长同种型表达的丧失，和/或 转变为小同种型的表达有助于肝肿瘤形成。在目标1中，我们将测试LAP 1是否 同种型变化是使用不同的小鼠模型驱动肝肿瘤形成的原因， 肝癌发生（目的1）。我们还将研究LAP 1在人HCC中的表达。在目标2中，我们将测试 假设LAP 1亚型通过表观遗传调节对基因表达有不同的影响， 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LAP 1同种型 选择性表达。这项拟议中的研究将揭示核被膜和肝细胞之间的新联系。 肿瘤，并提供了潜在的方法，以防止或逆转肝癌的慢性肝脏疾病的见解。 疾病

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.