赖氨酸代谢途径参与调控胃印戒细胞癌侵袭转移潜能的机制研究

As demonstrated by nutrients deprivation assays in our preliminary studies, we found that the survival of gastric signet ring cell carcinoma(SRC) depends on lysine metabolism, compared to other histological types of gastric adenocarcinoma. Acetyl-CoA, metabolic end-product of lysine, was observed in the tricarboxylic acid cycle and oxidative phosphorylation via isotopic tracing in the primary cells and cell lines of gastric SRC. Meanwhile, using mass spectrometry, we revealed that lysine-derived acetyl-CoA was involved in acetylation modification of Smoothened, an important component of Sonic hedgehog(Shh) signaling pathway. To determine whether lysine metabolism plays an important role in the progression of gastric SRC by providing sources of energy and regulating the Shh pathway, we will investigate the following questions: 1.the correlation between lysine metabolism and malignant phenotype of gastric SRC;2. the role of lysine metabolism in the process of energy supply in gastric SRC;3. the molecular mechanism of Smoothened acetylation by lysine metabolism, which may accelerate the invasive progression of gastric SRC. Therefore, this program would illustrate the potential mechanism of lysine metabolism in gastric SRC and provide a novel strategy for its treatment.

我们通过体外营养剥夺体系分析不同组织学类型胃癌细胞系的代谢特征，发现胃印戒细胞癌存活依赖赖氨酸代谢。在胃印戒细胞癌细胞中通过同位素跟踪实验发现赖氨酸代谢终产物乙酰辅酶A进入三羧酸循环和有氧氧化。同时，通过质谱我们发现赖氨酸来源乙酰辅酶A参与Sonic/hedgehog信号通路中重要组件Smoothed蛋白的乙酰化修饰。因此，我们提出赖氨酸代谢通过提供能量物质来源和调控Sonic/hedgehog通路在胃印戒细胞癌进展中发挥重要作用。本课题将对如下科学问题进行研究：1.赖氨酸代谢与胃印戒细胞癌恶性表型的相关性； 2.赖氨酸代谢在胃印戒细胞癌能量提供过程中的作用；3.赖氨酸代谢途径通过影响Smoothed蛋白的乙酰化促进胃印戒细胞癌侵袭潜能的分子机制。对这些问题的回答，将使我们进一步认识和理解赖氨酸代谢在胃印戒细胞癌恶性演进中的作用和意义，从而为有效治疗胃印戒细胞癌和改善预后提供新策略。

胃癌（Gastric cancer, GC）是危害人类健康的常见恶性肿瘤之一，目前在全球的癌症发病率居第五位，死亡率居第三位。代谢特征的改变是肿瘤细胞的重要特点之一，与肿瘤的发生发展密切相关。前期研究中我们发现剥夺赖氨酸导致胃印戒细胞癌细胞发生凋亡，而对其他类型胃腺癌细胞没有明显作用。在本项目中，我们发现印戒细胞癌细胞对赖氨酸的消耗量更大，赖氨酸代谢中间产物浓度更高，并伴随着更高表达水平的赖氨酸代谢酶。赖氨酸代谢限速酶AASS的表达水平与胃印戒细胞癌浸润深度及淋巴结转移密切相关。机制上，敲减AASS能够抑制胃印戒细胞癌中Smo蛋白的乙酰化，提示赖氨酸代谢介导的Smo蛋白乙酰化修饰对Shh通路非配体依赖性激活的重要影响。此外，我们还发现组蛋白甲基转移酶MLL1和转录因子SP1调节ANO1表达，促进胃癌侵袭和迁移；泛素连接酶HACE1介导细胞周期蛋白CCNC泛素化，通过调节胃癌细胞线粒体稳定性增加对顺铂的药物敏感性。我们的研究为胃癌的临床治疗提供了新的线索。