人结直肠癌中丝氨酸合成通路的代谢调控机制研究

项目名称： 人结直肠癌中丝氨酸合成通路的代谢调控机制研究

项目编号： No.81502096

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 王慧娟

作者单位： 河南大学

项目金额： 18万元

中文摘要： 代谢重编程是肿瘤的标志之一，大多数肿瘤表现出糖酵解效应的增强，而由糖酵解所衍生的代谢旁路的研究却知之甚少。课题组先前检测了127例直肠癌组织和43例对照组织的代谢谱变化，总结了相关的代谢通路图，发现糖酵解的支路-丝氨酸合成通路发生了较明显的变化，并且筛选出了其中起关键调控作用的代谢酶-磷酸丝氨酸氨基转移酶（PSAT1）和丝氨酸羟甲基转移酶（SHMT1/SHMT2），体内、外实验都证明其具有关键的调控作用。本研究以代谢酶的调控为切入点，探讨ATF4和G9A是通过怎样的方式来调控关键酶从而激活Serine合成通路，控制Serine的生成；Serine和PKM2之间又有怎样的调控方式，从而控制葡萄糖到底是通过何种途径为肿瘤细胞的生长提供能量和前体物质。通过以上研究，明确结直肠癌发生发展中代谢变化调控及相关分子机制，找出新的代谢靶点，为个体化医疗及小分子抑制剂的开发提供理论支持。

中文关键词： 结直肠癌；丝氨酸合成通路；代谢酶；代谢调控

英文摘要： Metabolic reprogramming has been proposed to be a hallmark of cancer. Most tumors exhibit increased glucose metabolism to lactate, yet the extent to which glucose-derived metabolic fluxes are used for alternative processes is poorly understood. We have reported the metabolic profiling of tissue samples between 127 rectal cancer subjects and 43 normal controls. Moreover, we summarize the related metabolic pathway of rectal cancer based on the modified metabolites. Surprisingly, we find a branch of the glycolysis-the serine biosynthetic pathway change obviously, which is consistent with the international research focusing on the metabolic regulation. So in this project, we focus on this pathway and find out the importance metabolic enzymes PSAT1, SHMT1 and SHMT2. The serine and glycine metabolic pathway play an important role in cancer cell rapid proliferation. PSAT1, SHMT1 and SHMT2 are probably as the key regulatory enzymes in vitro and in vivo experiments. Therefore, this project is focused on the regulation of metabolic enzymes. Combined with previous literatures, we want to find out how CRC cell activate the serine synthesis pathway through ATF4 and G9A. And also we will identify the regulation mechanism between serine and PKM2. As a result, we want to establish a complete metabolic regulatory network in CRC. Our work will not only get a major breakthrough in the underlying mechanism study of tumor metabolic regulation, but also shed light on the novel strategies and targets for CRC cancer therapy in the future.

英文关键词： Colorectal cancer;serine biosynthetic pathway;metabolic enzymes;metabolic regulation