The influence of an increased UDP-glucose ceramide glycosyltransferase (UGCG) gene expression on the development of hepatocellular carcinoma (HCC)

• Applicant: Dr. Marthe-Susanna Wegner
• Subject Area: Pathology ; Cell Biology
• Term: from 2019 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 436180912

Only 30 % of hepatocellular carcinoma (HCC) patients are eligible for surgical resection or transplantation. Besides, Sorafenib (NEXAVAR®) is the only approved drug for unresectable HCC. Sorafenib is effective in a minority of patients, which leads to a high death rate amongst HCC patients. Therefore, the development of new strategies for HCC prevention and treatment is necessary and its indispensable to identify the molecular mechanisms leading to tumor development. The UDP-glucose ceramide glucosyltransferase (UGCG) is increased in its expression in several cancer cell types, which is accompanied by induction of multidrug resistance. Gaucher disease is characterized by glucosylceramide (GlcCer) accumulation. Gaucher disease patients exhibit a hypermetabolism and increased risk for liver tumor development. In this respect the question arose to what extent the UGCG is involved in the regulation of hepatocyte metabolism and whether or not UGCG contributes to liver tumor pathology. Currently, only two studies indicate the involvement of UGCG in molecular mechanisms in HCC. In both studies liver cancer cells were used, what does not allow the differentiation between signaling pathways induced in the beginning of the process of cancerogenesis or maybe to a later time point. Mice with a liver-specific acetyl-CoA carboxylase (ACC1 and 2) knockout have an increased occurrence of liver tumor development. Ishibashi et. al. could already show that the UGCG is closely connected to ACC. This led to the question how UGCG and ACC are molecularly connected in the context of liver tumor development. Main goal of this study is to investigate the UGCG-dependent molecular mechanisms leading to liver tumor development. Therefore, in this study as compared to the mentioned studies UGCG is overexpressed in non-cancerous hepatocytes. Besides investigating UGCG-mediated induction of ROS defense mechanisms, the glutamine transporter translocation into the plasma membrane and altered signaling pathways should be investigated. In addition, the involvement of UGCG on glutamine oxidation in the citrate acid cycle is focus in this study. This will give information about whether or not the UGCG influences energy supply of hepatocytes. Furthermore, mitochondrial activity and biogenesis and induction of malignant processes in UGCG overexpressing hepatocytes should be analyzed. Beside the malignant cells, also immune cells, stromal cells and cells of the vascular system are involved in the process of tumor development. Main focus of the in vivo studies is to investigate the influence of an UGCG overexpression on immune response modulating processes.In summary, UGCG-dependent mechanisms presumably leading to liver cell carcinogenesis should be analyzed to develop new strategies for prevention and treatment of HCC.

• DFG Programme: Research Fellowships
• International Connection: Australia
• Host: Professor Dr. Kyle L. Hoehn