Mechanisms of lipid droplet trafficking in hepatocellular carcinoma

项目摘要/摘要 肝细胞癌是最常见的肝癌形式，排在第四位。 是全球癌症死亡的主要原因。肝癌的发病率正在上升，成为关键的危险因素 包括肥胖和大量饮酒的速度比以往任何时候都要快 在此之前。这些危险因素导致肝脏脂肪变性和脂肪性肝炎，以极端 肝细胞内脂滴积聚，导致肝硬变和肝细胞癌。而当 脂质合成是肝细胞癌中已被描述的表型，低密度脂蛋白在肿瘤增殖中的作用 人们对它们的形成和生长知之甚少。我们实验室的初步数据表明， 小的GTP酶Rab5定位于LDS，并在向LDS的贩运中发挥关键作用 溶酶体，其中LDS被溶酶体酸性脂肪酶(LAL)分解。此外，两个Rab5 和LAL在肝癌中的表达增加，这与细胞生物学研究一致 与正常肝细胞相比，肝细胞癌细胞系的吞脂性增强。这些数据支持 Rab5-LD相互作用通过溶酶体分解代谢驱动肝癌生长的假说。 在目标1中，我们将确定肝癌中Rab5与LDS结合的机制，以及这是如何实现的 相互作用影响癌细胞的能量和增殖。在目标2中，我们将确定 睡美人体内Rab5介导的脂噬作用对肝癌生长的影响 转座子转座酶(SBTT)小鼠模型，在该模型中癌基因被运送到肝细胞 通过流体动力性尾静脉注射(HTVI)。从拟议的研究中获得的结果将 提供对脂滴运输和分解代谢的机械理解 肝细胞癌进展。此外，这项研究将有助于未来的发展。 较大规模的研究项目拨款申请。

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.