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

UDP-葡萄糖神经酰胺糖基转移酶（UGCG）基因表达增加对肝细胞癌（HCC）发展的影响

基本信息

批准号：
436180912
负责人：
Dr. Marthe-Susanna Wegner
金额：
--
依托单位：
School of Biotechnology and Biomolecular Sciences
依托单位国家：
德国
项目类别：
Research Fellowships
财政年份：
2019
资助国家：
德国
起止时间：
2018-12-31 至 2021-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/436180912?language=en
关键词：
influence increased UDP glucose ceramide

项目摘要

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.

只有30%的肝细胞癌患者有资格接受手术切除或移植。此外，索拉非尼(Nexavar®)是唯一被批准用于治疗无法切除的肝癌的药物。索拉非尼对少数患者有效，导致肝癌患者的高死亡率。因此，开发新的肝癌防治策略是必要的，也是识别导致肿瘤发生的分子机制所不可缺少的。UDP-葡萄糖神经酰胺葡萄糖基转移酶(UGCG)在多种肿瘤细胞中表达增加，并伴随着多药耐药的诱导。高谢病的特点是葡萄糖神经酰胺(GlcCer)蓄积。高谢病患者表现出高代谢，增加了发生肝肿瘤的风险。在这方面，问题出现了UGCG在多大程度上参与了肝细胞代谢的调节，以及UGCG是否有助于肝脏肿瘤的病理。目前，只有两项研究表明UGCG参与了肝细胞癌的分子机制。在这两项研究中，都使用了肝癌细胞，这不允许在癌变过程的开始或以后的时间点诱导信号通路之间的分化。具有肝脏特异性乙酰辅酶A羧基酶(ACC1和2)基因敲除的小鼠发生肝脏肿瘤的几率增加。石桥等人。艾尔可能已经表明UGCG与ACC密切相关。这就引出了UGCG和ACC在肝脏肿瘤发展中是如何在分子上联系在一起的问题。本研究的主要目的是探讨UGCG依赖导致肝肿瘤发生的分子机制。因此，在本研究中，与上述研究相比，UGCG在非癌肝细胞中过表达。除了研究UGCG介导的ROS防御机制外，还应研究谷氨酰胺转运蛋白转运蛋白进入质膜和改变信号通路。此外，UGCG在谷氨酰胺氧化柠檬酸循环中的作用也是本研究的重点。这将提供关于UGCG是否影响肝细胞能量供应的信息。此外，还应分析UGCG过表达肝细胞的线粒体活性、生物发生和恶性过程的诱导。除了恶性细胞外，免疫细胞、间质细胞和血管系统细胞也参与了肿瘤的发展过程。体内研究的主要焦点是研究UGCG过表达对免疫反应调节过程的影响。综上所述，应分析UGCG依赖的导致肝细胞癌变的机制，以开发预防和治疗肝癌的新策略。