ASS1介导的精氨酸代谢促进肝癌转移的机制研究

The unique energy metabolism of HCC can promote its biological behavior such as proliferation, invasion and metastasis. In preliminary work, by comparing the metabolic characteristics of HCC tissues with different degrees of metastasis, the applicant found that the difference in arginine-related metabolism was the most obvious in the patients with different degrees of metastasis. Arginine is a semi-essential amino acid and ASS1 is the key rate-limiting enzyme in its synthesis. Based on the previous metabolomics data, combined with the TCGA database, this project intends to verify the hypothesis by in vivo and in vitro experiments: the different expression levels of ASS1 can regulate the synthesis of arginine, thereby increasing the exogenous arginine uptake of tumor cells. Tumor cells compete for nutrients in the microenvironment, leading to immunosuppression and promoting metastasis. This project can not only clarify the mechanism of ASS1 mediating arginine metabolism to promote HCC metastasis, but also provide a new theoretical basis for metabolic therapy of HCC related to arginine deprivation, and exploration of individualized programs.

肝癌独特的能量代谢的特征能够促进其增殖、侵袭、转移等生物学行为。前期通过比较转移程度不同的肝癌组织代谢特征，申请者发现精氨酸相关代谢在转移高低程度不同患者间的差异最为明显。精氨酸是一种半必需氨基酸，ASS1是其合成的关键限速酶。在前期代谢组学数据的基础上，结合TCGA数据库，本项目拟通过体内、体外实验验证假说：ASS1的表达差异能够调控精氨酸的合成，从而增加肝癌细胞对外源性精氨酸摄取的依赖，竞争微环境中的营养物质，从而导致免疫抑制，促进转移。本项目不仅能明确ASS1介导的精氨酸代谢促进肝癌转移的机制,而且能够为肝癌精氨酸剥夺相关的代谢治疗提供新的理论依据，探索个体化方案。

肿瘤代谢重编程是肿瘤发生发展过程中的的重要特征之一。研究者利用代谢组学技术分析转移潜能不同的肝癌组织代谢水平，发现了差异代谢物精氨酸及精脯氨酸代谢通路中相关基因如ASS1、SLC7A1、PYCR1在肝癌的增殖及侵袭转移中发挥了重要的作用。研究发现精氨酸具有促进肿瘤增殖、侵袭转移的功能，高转移潜能的肝癌组织中存在精氨酸的异常累积，其主要是由SLC7A1介导的对外源性精氨酸外源性摄取来调控。后续通过体内外实验研究阐明了精脯氨酸代谢在HCC细胞内发挥促进恶性表型的作用机制是依赖于PYCR1的表达，为精氨酸剥夺治疗与线粒体裂解抑制剂Mdivi-1的联合应用提供了理论依据。