SGLT1调控糖酵解促进胃癌生长的机制研究

Aerobic glycolysis, which is known as the Warburg effect, plays an important role in tumorigenesis and progression of cancer. Sodium glucose cotransporter-1 is located in the membrane of cell, which plays an active role in the transport of glucose. The expression of SGLT1 in gastric cancer and its relationship with the biological behavior of gastric cancer have not been reported before. The main purpose of this study is to explore the expression of SGLT1 in gastric cancer and to clarify whether it is involved in the regulation of aerobic glycolysis and growth of gastric cancer cells. The results of previous studies suggested that the expression level of SGLT1 in gastric cancer is not completely dependent on EGFR regulation, there are other regulatory mechanisms. Therefore, on the basis of previous studies, this study is 1) to explore the expression of SGLT1 in gastric cancer and analyze the relationship between expression level of SGLT1 and clinical pathological characteristics of gastric cancer; 2) To explore the changes of glucose level, energy metabolism, proliferation of gastric cancer cells which regulated by SGLT1; 3) To explore the regulation mechanism of SGLT1 in gastric cancer. This study could reveal the important role of SGLT1 in the regulation of aerobic glycolysis and growth of gastric cancer, which may provide a scientific basis for the therapeutic treatment targeted SGLT1 in gastric cancer.

有氧糖酵解，即Warburg效应在肿瘤发生发展过程中发挥重要作用。钠糖共同转运体-1（Sodium Glucose Cotransporter-1）位于细胞膜，起主动转运葡萄糖的作用。SGLT1在胃癌中的表达及其与胃癌细胞生物学行为的研究未有报道。本课题的主要目的在于探究SGLT1在胃癌中的表达情况并明确其是否参与调控有氧糖酵解，从而影响胃癌细胞生长。本课题组前期研究结果提示SGLT1在肿瘤中的表达水平并不完全依赖EGFR调控，尚存在其他的表达调控机制。本研究拟进一步探究：1）SGLT1在胃癌中的表达情况并分析其与胃癌临床病理特征的关系；2）探究SGLT1的变化对胃癌细胞葡萄糖的转运吸收及能量代谢的变化以及增殖的影响；3）探究SGLT1在胃癌中的表达调控机制。本研究将揭示SGLT1在调控胃癌有氧糖酵解及细胞生长方面的重要作用，为以SGLT1为靶点的胃癌治疗提供科学依据。

本课题基于前期的研究基础，特别是糖酵解与肿瘤生长的调控关系，聚焦SGLT1（Sodium Glucose Cotransporter-1），探究其是否在胃癌生长过程中发挥重要作用。研究结果显示，SGLT1在胃癌中的表达水平明显高于癌旁正常组织，其与胃癌患者的病理学特征密切相关，SGLT1高表达胃癌患者的生存时间明显少于SGLT1低表达的胃癌患者，提示其与胃癌患者的不良预后相关。运用CRISPR/Cas9技术敲低SGLT1表达后，能明显促进胃癌细胞的凋亡，抑制胃癌细胞的生长，提示其在胃癌生长中发挥了重要作用。上述一系列生物表型的变化趋势均提示SGLT1在胃癌细胞的生长过程中发挥了重要的作用。自身调控机制上，研究发现SGLT1启动子区存在p53转录因子结合位点，其表达水平受p53负向调控。通过基因组学、蛋白组学等高通量技术整合相关数据发现，敲除SGLT1后，TAK1（TGFβ-activated kinase 1）的表达水平亦显著下调，提示其可能是SGLT1的下游靶分子。TAK1具有丝氨酸/苏氨酸蛋白激酶活性，功能上位于MAPK和NF-κB信号通路的共同上游，参与包括细胞凋亡在内的多种病理生理过程，是细胞内的重要信号转导通路。后续研究将聚焦SGLT1下游相关靶分子TAK1，厘清SGLT1-TAK1信号通路以及SGLT1对TAK1的调控机制，进一步阐明SGLT1在胃癌生长中的重要作用。