SLC38A6通过调控天冬氨酸介导的嘧啶合成促进肝癌生长的机制研究

嘧啶是生命最基本的物质单位之一，其合成代谢异常与肿瘤生长密切相关，然而调控肝癌嘧啶合成代谢的机制尚不明确。精氨琥珀酸合酶（ASS1）缺失可上调天冬氨酸（Asp）含量并促进肿瘤细胞嘧啶合成，ASS1转录活性受PI3K/AKT调控。前期研究发现SLC38A6能够磷酸化AKT、抑制ASS1转录并上调肝癌嘧啶合成相关代谢产物，敲低SLC38A6抑制肝癌细胞增殖。初步表明SLC38A6通过调控嘧啶合成代谢参与肝癌生长进程。目前SLC38A6对肝癌代谢的影响尚未有报道。本研究拟采用稳定同位素标记辅助的靶向代谢组学等技术，阐明SLC38A6与Asp、嘧啶合成的关系及在肝癌生长中的作用；探讨SLC38A6是否通过调控Asp介导的嘧啶合成影响肿瘤细胞增殖；明确ASS1是SLC38A6调控嘧啶合成的关键靶点。本项目的实施从肿瘤代谢视角明确SLC38A6在肝癌生长过程中的具体作用，为肝癌靶向治疗提供新策略。

Pyrimidine is one of the most basic material units of life, and its anabolic abnormality is closely related to tumor growth. However, the mechanism of regulating pyrimidine anabolism in liver cancer is still unclear. Deletion of Arginine succinate synthase (ASS1) can up-regulate the content of aspartate (Asp) and promote pyrimidine synthesis in tumor cells; the transcriptional activity of ASS1 is regulated by PI3K/AKT. Previous studies have found that SLC38A6 can phosphorylate AKT, inhibit ASS1 transcription and up-regulate metabolites related to pyrimidine synthesis in liver cancer; knock down SLC38A6 inhibits the proliferation of liver cancer cells. Preliminary experiments show that SLC38A6 participates in the growth of liver cancer by regulating pyrimidine anabolism. At present, the effect of SLC38A6 on liver cancer metabolism has not been reported yet. This study intends to use stable isotope labeling-assisted targeted metabolomics to clarify the relationship between SLC38A6 and Asp and pyrimidine synthesis, and its role in the growth of liver cancer; To verify whether SLC38A6 affects tumor cell proliferation by regulating Asp-mediated pyrimidine synthesis; To determine whether ASS1 is the key target of SLC38A6 to regulate pyrimidine synthesis. The implementation of this project will clarify the specific role of SLC38A6 in the growth of liver cancer from the perspective of tumor metabolism, and provide novel strategies for targeted therapy of liver cancer.