Nuclear envelope and predisposition to hepatic neoplasia

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.