溶质载体蛋白SLC25A21调控肿瘤代谢重编程介导KRAS突变型结直肠癌演进的分子机制

代谢重编程是恶性肿瘤的重要特征之一，干预肿瘤代谢是肿瘤治疗的一个有效策略，但KRAS突变的结直肠癌代谢相关通路仍有待深入研究。我们前期研究发现：SLC25A21高表达可特异性抑制KRAS突变的结直肠癌细胞的增殖和转移，其低表达与KRAS突变患者预后不良相关；SLC25A21通过调节α铜戊二酸的流动影响肿瘤代谢和KRAS活性；SLC25A21可能受甲基化调控。由此提出“在甲基化调控下，SLC25A21通过调节肿瘤代谢重编程介导KRAS突变型结直肠癌演进”的科学假说。本课题拟在前期基础上，利用体内外实验、转基因动物等方法进一步鉴定SLC25A21在KRAS突变型结直肠癌中的作用及对KRAS突变结直肠癌靶向药物疗效的影响；通过检测代谢指标及同位素示踪代谢组学变化明确其调节结直肠癌代谢重编程的途径。本研究将从代谢重编程的角度解析结直肠癌发生发展的分子机制，为KRAS突变的结直肠癌的诊疗提供新思路。

Metabolic reprogramming has been proposed to be a hallmark of cancer, and metabolic interventions are now emerging as potential therapeutic strategies for cancer treatment. However, a systematic characterization of the metabolic pathways active in CRC with KRAS mutation is currently lacking. Our preliminary experiment results showed that the expression of the SLC25A21 was down-regulated in CRC tissues and cells. The downregulation of SLC25A21 was associated with the poor prognosis of CRC patients with KRAS mutation. The SLC25A21 overexpression could selectively inhibit the proliferation, invasiveness and mobility of KRAS-mutant CRC cells, while it had little effect in KRAS wild-type CRC cells. The dysregulation of SLC25A21 expression regulated glutamine metabolism by inducing 2-oxoglutarate (α-KG) fluxing between mitochondrial and cytoplasm and KRAS activity in KRAS-mutant CRC cells. The expression level of SLC25A21 was up-regulated by 5-aza-dC treatment, a DNA methyltransferase inhibitor. Therefore, we propose a hypothesis that DNA methylation-regulated SLC25A21 induces metabolism reprogramming to modulate KRAS-mutant CRC progression. In this study, we will evaluate the functions of SLC25A21 in KRAS-mutant CRC and the efficiency of SLC25A21 on the molecular targeting drugs in KRAS-mutate CRC in vivo and in vitro through gain- and loss- of function model, and transgenic mouse models. We will investigate the effects of SLC25A21 on metabolic reprogramming via metabolomic analysis using isotopes as a tracer. The research will contribute to reveal the molecular mechanisms of CRC carcinogenesis and progression from a new point of view about metabolic reprogramming, which providing new targets for diagnosis and therapy for KRAS-mutant CRC.