Nuclear envelope and predisposition to hepatic neoplasia

项目总结 慢性肝病，如非酒精性脂肪性肝炎，显著增加了肝硬化和 肝细胞癌(HCC)。然而，导致肝细胞癌的潜在机制和基因改变 人们对慢性肝病的发生发展知之甚少。因此，迫切需要更好地 了解肝细胞损伤易感肝细胞癌发生的基本机制。这 Proposal研究了新的机制，可以将核膜的变化与易感性联系起来 肝细胞癌。层相关多肽1(LAP1)是内核膜上相互作用的一种完整蛋白质 染色质。我们先前的研究表明，肝细胞中LAP1的缺失会改变肝脏的脂质代谢。 我们新的初步数据证明了LAP1在肝癌易感性中的另一个独特作用。LAP1正在经历 在小鼠模型中，细胞分化过程中的异构体转换和异构体表达的显著逆转 在肝癌和人类肝细胞癌中也是如此。此外，我们已经证明了LAP1从小鼠身上耗尽 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 在肿瘤出现之前，与肿瘤发生有关的特定遗传基因。这些结果使我们得到了 假设LAP1调节肝细胞分化和长异构体和/或表达缺失 转换为小异构体的表达有助于肝脏肿瘤的发生。在目标1中，我们将测试LAP1 在不同的小鼠模型中，亚型变化是导致肝肿瘤发生的原因之一 肝癌发生(目标1)。我们还将检测LAP1在人肝细胞癌中的表达。在目标2中，我们将测试 LAP1亚型通过差异表观遗传调控对基因表达有不同影响的假说 与染色质或染色质修饰蛋白结合。我们将使用肝癌的体内和细胞培养模型和 检测LAP1亚型在人诱导的多能干细胞中的肝细胞分化 有选择地表达。这项拟议的研究将揭示核膜和肝脏之间的新联系。 并为预防或逆转慢性肝组织中肝细胞癌的潜在方法提供见解 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.