LACTB-SCD1轴参与代谢重编程调控胃癌细胞腹膜转移的机制研究

代谢异常与胃癌转移密切相关，但代谢异常与胃癌腹膜转移之间调控机制尚未明确。申请人通过测序筛选发现高脂饲养鼠腹膜转移瘤中低表达基因β-内酰胺酶(Lactamase Beta, LACTB)，其蛋白定位于线粒体中调控脂代谢。LACTB在人胃癌腹膜转移灶中表达低于配对原发灶而且LACTB高表达胃癌患者预后相对较好。体内实验证实过表达LACTB抑制高脂饲养鼠腹膜转移瘤形成，转录组联合代谢组学分析证实LACTB负向调控SCD1抑制不饱和脂肪酸合成和糖酵解过程，而且SCD1增强胃癌细胞迁移能力。本研究提出“LACTB-SCD1轴通过参与代谢重编程调控胃癌细胞腹膜转移”科学假设，拟通过体内外实验验证LACTB负向调控SCD1抑制胃癌细胞腹膜转移能力，探索LACTB负向调控SCD1的分子机制以及LACTB-SCD1轴抑制胃癌细胞腹膜转移的代谢调控机制，以上研究有望为探索胃癌腹膜转移精准治疗策略奠定基础。

Metabolic disorder is closely associated with gastric cancer (GC) metastasis, while the mechanism by which metabolic disorder regulate peritoneal metastasis of GC is still unclear. Lactamase Beta (LACTB), of which protein located in mitochondrion and modulate lipid metabolism, have been identified to be low-expressed in high fat diet (HFD) groups by RNA-sequencing technology. The protein level of LACTB in peritoneal foci was lower than that in paired primary tumor of gastric cancer patients and overexpression of LACTB was identified as a predictor of relatively better prognosis. And then in vivo assay have confirmed that LACTB could inhibit peritoneal metastasis of GC cells in HFD-mice, transcriptomics and metabolomics analysis revealed that LACTB inhibit synthesis of unsaturated fatty acid and glycolysis via negatively regulating SCD1 expression, besides, SCD1 could promote migration of GC cells. Scientific hypothesis of this study is that LACTB-SCD1 axis regulate peritoneal metastasis of GC cells via modulating metabolic reprogramming. To this end, whether LACTB inhibit peritoneal metastasis of GC cells via negatively regulating SCD1, the molecular mechanism by which LACTB negatively regulate SCD1 expression and the metabolic mechanism by which LACTB-SCD1 axis inhibit peritoneal metastasis of GC cells will be manifested by in vivo and in vitro assays. The above-mentioned study would become cornerstone for precise therapeutic strategy for peritoneal metastasis of GC.