基于蛋白质组学和脂质组学研究脂肪酸2-羟化酶调控肿瘤细胞能量代谢的分子机制

Dysfunction of energy metabolism is popular in various cancer cells. Fatty acid 2-hydroxylase (FA2H) is a recently identified NAD(P)H-dependent enzyme, which catalyze the formation of 2-hydroxy fatty acid(2-OHFA). We found that in adipocyte FA2H regulate the glucose and lipid metabolism by increasing the fluidity of membrane lipid raft. This indicates there exists the relationship among FA2H, caveolae, and cellular energy metabolism. Western blot experiment indicates FA2H is highly expressed in human colorectal cancer cell. But the underlying role and mechanism of FA2H in colorectal cancer development is still poorly clear. Based on these findings, we will here study on the mechanism of FA2H in modulation of cellular energy metabolism in colorectal cancer cell using the combination of SILAC-based quantitative proteomics, MS-based lipid analysis technique, bioinformatics, and molecule biological methods. We here hypothesize that caveolae and protein palmitoylation mediate the regulation of cellular energy metabolism by FA2H, based on the fact that 2-OHFA, the catalytic product of FA2H, is involved in the production of 2-OH sphingolipid and the process of protein palmitoylation. Our study will help us understand the physiological and pathological significance of FA2H in colorectal cancer development and provide information for seeking novel theraputic target for colorectal cancer cell.

细胞能量代谢异常是肿瘤细胞的特征之一。脂肪酸2-羟化酶（FA2H）是近年发现的一种NAD(P)H依赖性酶，可催化2-羟基脂肪酸（2-OHFA）生成。申请人近期研究发现FA2H通过调节胞膜脂筏的流动性来调控脂肪细胞的糖脂代谢，提示FA2H、caveolae、细胞能量代谢之间存在某种必然联系。我们的预实验证明FA2H在人结肠癌细胞中高表达，但其在肿瘤发生发展尤其在结直肠癌中的作用及机制尚不清楚。基于此，本项目拟利用SILAC定量蛋白质组学、基于质谱的脂质分析、分子生物学等多种研究手段，围绕FA2H催化产物2-OHFA两种可能的代谢去路-生成2-羟基鞘脂和参与蛋白质棕榈酰化修饰，研究FA2H调控结肠癌细胞能量代谢的分子机制。我们认为caveolae和蛋白质棕榈酰化修饰介导了FA2H的调控过程。这些研究将有助于理解FA2H在结肠癌发生发展中的生理学和病理学意义，并为寻找结肠癌治疗新靶点提供新思路。

结直肠癌是全球常见的恶性肿瘤之一，具有易转移易复发的特点，其发病率和死亡率在癌症中均位居前列。脂肪酸-2-羟化酶(fatty acid-2-hydroxylase, FA2H)可催化2-羟基脂肪酸的生成，参与调控肿瘤细胞增殖、凋亡、迁移和侵袭等生理过程。代谢重编程是肿瘤细胞的一个显著特征。肿瘤细胞因其异质性，使其代谢方式更为复杂。本项目借助基于TMT和SILAC标记的定量蛋白质组学和分子生物学技术，以人结直肠癌LoVo和HT-29细胞系作为研究对象，揭示了FA2H通过介导人结肠癌细胞代谢重编程调控其迁移侵袭的潜在分子机制。 研究发现FA2H的调控机制存在细胞异质性的特点，与肿瘤细胞所处的微环境密切相关。本项目的研究结果为挖掘FA2H在结肠癌发生发展中的生理学和病理学意义，发现结肠癌治疗的新靶点提供了新的思路。