Mechanisms of lipid droplet trafficking in hepatocellular carcinoma

项目总结/摘要 肝细胞癌（HCC）是最常见的肝癌形式， 是全球癌症死亡的主要原因。肝癌的发病率作为关键的危险因素正在上升 包括肥胖和大量饮酒， 以前这些危险因素驱动肝脂肪变性和脂肪性肝炎，其特征是 肝细胞中的脂滴（LD）积累，导致肝硬化和HCC。而 脂质合成是HCC中一种被充分描述的表型，LD在肿瘤增殖中的作用 形成和生长是知之甚少。我们实验室的初步数据表明， 小型GTTRB 5定位于LDs，并在贩运到 溶酶体，其中LD被溶酶体酸性脂肪酶（LAL）分解代谢。此外，Rab 5 和LAL表达在HCC肿瘤中增加，与细胞生物学研究一致 显示了HCC细胞系相对于正常肝细胞的脂肪吞噬性升高。这些数据支持 Rab 5-LD相互作用通过溶酶体催化作用驱动HCC肿瘤生长的假设。 在目标1中，我们将确定Rab 5与肝细胞癌中LDs结合的机制，以及这是如何通过与LDs结合来实现的。 相互作用影响癌细胞能量学和增殖。在目标2中，我们将确定 Rab 5介导脂肪吞噬作用对肝癌生长影响 转座子转座酶（SBTT）小鼠模型，其中癌基因被递送至肝细胞 通过流体动力学尾静脉注射（HTVI）。从拟议的研究中获得的结果将 提供了一个机制的理解脂滴运输和catenin 肝细胞癌进展。此外，这项研究将有助于未来的发展， 更大的研究项目资助申请。

Project Summary/Abstract Hepatocellular carcinoma (HCC) is the most common form of liver cancer and fourth leading cause of cancer deaths worldwide. The incidence of HCC is rising as key risk factors including obesity and heavy alcohol consumption are accelerating at rates greater than ever before. These risk factors drive hepatic steatosis and steatohepatitis, marked by the extreme accumulation of lipid droplets (LDs) in hepatocytes, leading to cirrhosis and HCC. While lipid synthesis a well-described phenotype in HCC, the role of LDs in propagating tumor formation and growth is poorly understood. Preliminary data from our laboratory suggests that the small GTPase Rab5 localizes to LDs and plays a critical role in trafficking to the lysosome, where LDs are catabolized by lysosomal acid lipase (LAL). Moreover, both Rab5 and LAL expression are increased in HCC tumors, consistent with cell biological studies showing elevated lipophagy in HCC cell lines vs normal hepatocytes. These data support the hypothesis that Rab5-LD interaction drives HCC tumor growth via lysosomal catabolism. In Aim 1, we will determine the mechanisms of Rab5 binding to LDs in HCC, and how this interaction impacts cancer cell energetics and proliferation. In Aim 2, we will determine the impact of Rab5-mediated lipophagy on HCC tumor growth in vivo using a sleeping beauty transposon transposase (SBTT) mouse model in which oncogenes are delivered to hepatocytes via hydrodynamic tail vein injection (HTVI). The results gained from the proposed research will provide a mechanistic understanding of lipid droplet trafficking and catabolism in hepatocellular carcinoma progression. Moreover, this research will aid in future development of larger research project grant applications.