谷氨酰胺合成酶对胃癌细胞恶性生物学行为的影响及其机制研究

Altered metabolism is a generally regarded hallmark of cancer. Deciphering molecular mechanism underlying metabolic reprogramming in tumor cells may yield promising therapeutic and diagnostic utilities. Glutamine plays critical roles in tumor initiation and progression. The de novo glutamine synthesis is mediated by glutamine synthetase (GS). It has been shown that oncogenic c-Myc could induce the expression of GS in multiple tumors, such as breast cancer, lung cancer, pancreatic cancer and liver cancer. GS was found to play a predominant pro-oncogenic role in these tumors. However, we found that GS was downregulated in clinical gastric cancer sample and gastric cancer cell lines compared with normal control in our previously studys. It suggested that GS might be a potential tumor suppressor in gastric cancer. Moreover, we found that downregulation of GS may be related to activation of glutamatergic signaling in gastric cancer cells. In this study, we sought to further elucidate the effects of glutamine synthetase on malignant biological behaviors of gastric cancer cells. Meanwhile, the mechanism underlying inhibitory effects of GS on gastric cancer will also be investigated. Overall, our work may unveil molecular events in gastric cancer that have implications for targeting a unique aspect of this disease.

代谢异常是肿瘤细胞重要的生物学特征之一，深入揭示肿瘤细胞的代谢过程及其分子机制对开发新型抗肿瘤策略具有重要意义。谷氨酰胺合成酶（Glutamine Synthetase，GS）是催化合成肿瘤细胞重要营养物质——谷氨酰胺的关键酶。研究报道，在多种类型肿瘤（如乳腺癌、胰腺癌、肝癌、肺癌等）中，癌基因c-Myc可诱导肿瘤细胞上调表达GS，且GS在这些类型肿瘤中被证明发挥促癌效应。然而，申请人通过分析胃癌临床标本及细胞系发现，GS在胃癌中表达下调，提示GS在胃癌中可能并不发挥促癌效应，相反其或具有潜在的胃癌抑制功能。进一步研究发现，GS表达下调可能有助于胃癌细胞谷氨酸受体信号通路的激活。据此，本课题拟进一步探究GS的表达变化对胃癌细胞增殖、侵袭、转移、放化疗抵抗等恶性生物学行为的影响，并通过研究GS对胃癌细胞谷氨酸受体信号通路的调控，阐明其分子机制，为胃癌的诊断及治疗提供新的思路。

代谢异常是肿瘤细胞重要的生物学特征之一，深入揭示肿瘤细胞的代谢过程及其分子机制对开发新型抗肿瘤策略具有重要意义。谷氨酰胺合成酶（glutamine synthetase，GS），又名谷氨酸-氨连接酶（Glutamate-Ammonia Ligase，GLUL）是催化合成细胞重要营养物质谷氨酰胺的关键酶。研究报道，在多种类型肿瘤（如乳腺癌、胰腺癌、肝癌、肺癌等）中，GLUL被证明发挥促癌的生物学效应。本研究探索了GLUL在胃癌中的表达变化及其对胃癌细胞增殖、侵袭、转移、放化疗抵抗等恶性生物学行为的影响，并重点从GLUL参与介导胃癌细胞免疫逃逸的角度出发，阐述了GLUL在胃癌恶性生物学行为中的作用及调节机制。方法：通过生物信息学、蛋白质免疫印迹、免疫组化等方法分析GLUL在人胃癌组织中的表达变化及与免疫细胞浸润程度（尤其是T细胞）之间的相关性；构建GLUL过表达的胃癌细胞株；通过T细胞免疫杀伤等功能学实验探究GLUL参与胃癌细胞免疫逃逸的相关机理。结果：胃癌组织中GLUL的表达量明显低于正常胃粘膜组织，GLUL的表达与T细胞的数量具有明显相关性，高表达GLUL可增强胃癌细胞对效应性T细胞的免疫应答。本研究将肿瘤细胞代谢重塑与肿瘤免疫逃逸相结合，对深入理解胃癌的发生发展及相关分子调控机制具有重要意义，并可为开发新型的胃癌治疗策略提供了理论支撑。