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

只有30%的肝细胞癌（HCC）患者适合手术切除或移植。此外，索拉非尼（NEXAVAR®）是唯一批准用于不可切除HCC的药物。索拉非尼在少数患者中有效，这导致HCC患者的高死亡率。因此，发展肝癌预防和治疗的新策略是必要的，并且其不可或缺的是确定导致肿瘤发展的分子机制。UDP-葡萄糖神经酰胺葡糖基转移酶（UGCG）在几种癌细胞类型中的表达增加，这伴随着多药耐药的诱导。戈谢病的特征在于葡糖神经酰胺（GlcCer）积累。戈谢病患者表现出高代谢和肝肿瘤发展的风险增加。在这方面的问题出现了什么程度的UGCG参与肝细胞代谢的调节，以及是否UGCG有助于肝肿瘤的病理。目前，只有两项研究表明UGCG参与HCC的分子机制。在这两项研究中，使用了肝癌细胞，这不允许在癌症发生过程的开始或可能到稍后的时间点诱导的信号通路之间的分化。肝脏特异性乙酰辅酶A羧化酶（ACC 1和2）敲除的小鼠肝脏肿瘤发生率增加。石桥等这就引出了一个问题，即UGCG和ACC在肝肿瘤发展的背景下是如何分子连接的。本研究的主要目的是探讨UGCG依赖的分子机制，导致肝脏肿瘤的发展。因此，在本研究中，与上述研究相比，UGCG在非癌性肝细胞中过表达。除了研究UGCG介导的ROS防御机制的诱导，谷氨酰胺转运蛋白易位到质膜和改变的信号转导途径应进行研究。此外，UGCG对柠檬酸循环中谷氨酰胺氧化的参与也是本研究的重点。这将提供关于UGCG是否影响肝细胞能量供应的信息。此外，应分析UGCG过表达肝细胞中的线粒体活性和生物发生以及恶性过程的诱导。除了恶性细胞之外，免疫细胞、基质细胞和血管系统的细胞也参与肿瘤发展的过程。体内研究的主要焦点是研究UGCG过表达对免疫应答调节过程的影响，总之，应分析UGCG依赖性的肝细胞癌变机制，以开发新的预防和治疗HCC的策略。

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.