Department of Gastrointestinal Surgery, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, No. 98, Nantong West Road, Guangling District, Yangzhou, Jiangsu, 225001, P.R. China.
Department of Gastrointestinal Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University & Shandong Academy of Medical Science, Jinan, Shandong, 270000, P.R. China.
Funct Integr Genomics. 2024 Nov 15;24(6):214. doi: 10.1007/s10142-024-01495-9.
Gastric cancer (GC) is the third leading cause of death in developed countries. The reprogramming of energy metabolism represents a hallmark of cancer, particularly amplified dependence on aerobic glycolysis. Here, we aimed to illustrate the functional role of glutamate ionotropic receptor N-methyl-D-aspartate type subunit 2D (GRIN2D) in the regulation of glycolysis in GC and the mechanisms involved. Differentially expressed genes were analyzed using the GEO and GEPIA databases, followed by prognostic value prediction using the Kaplan-Meier Plotter database. The effect of GRIN2D knockdown on the malignant behavior and glycolysis of GC cells was explored. GRIN2D expression was upregulated in GC cells and promoted the malignant behavior of GC cells by activating glycolysis. Class E basic helix-loop-helix protein 40 (BHLHE40) was overexpressed in GC cells and mediated transcriptional activation of GRIN2D. The anti-tumor effects of BHLHE40 knockdown on GC cells in vitro and in vivo were reversed by GRIN2D overexpression. Knockdown of GRIN2D or BHLHE40 downregulated the expression of mRNA of electron transport chain subunits and phosphorylation of p38 MARK and inhibited calcium efflux in GC cells. Overexpression of GRIN2D promoted calcium efflux, phosphorylation of p38 MARK protein, and proliferation of GES1 cells. Altogether, the findings derived from this study suggest that BHLHE40 knockdown suppresses the growth, mobility, and glycolysis of GC cells by inhibiting GRIN2D transcription and disrupting the BHLHE40/GRIN2D axis may be an attractive therapeutic strategy for GC.
胃癌（GC）是发达国家中第三大死亡原因。能量代谢的重编程代表了癌症的一个标志，特别是对有氧糖酵解的依赖性增强。在这里，我们旨在阐明谷氨酸离子型受体 N-甲基-D-天冬氨酸 2D 型亚基（GRIN2D）在 GC 中调节糖酵解的功能作用及其涉及的机制。使用 GEO 和 GEPIA 数据库分析差异表达基因，然后使用 Kaplan-Meier Plotter 数据库预测预后价值。探讨了 GRIN2D 敲低对 GC 细胞恶性行为和糖酵解的影响。GRIN2D 在 GC 细胞中表达上调，并通过激活糖酵解促进 GC 细胞的恶性行为。E 类碱性螺旋-环-螺旋蛋白 40（BHLHE40）在 GC 细胞中过表达，并介导 GRIN2D 的转录激活。BHLHE40 敲低对 GC 细胞的体内外抗肿瘤作用被 GRIN2D 过表达逆转。GRIN2D 或 BHLHE40 的敲低下调了 GC 细胞中电子传递链亚基的 mRNA 表达和 p38MARK 的磷酸化，并抑制了 GC 细胞中的钙外流。GRIN2D 的过表达促进了钙外流、p38MARK 蛋白的磷酸化和 GES1 细胞的增殖。总之，本研究的结果表明，BHLHE40 敲低通过抑制 GRIN2D 转录抑制 GC 细胞的生长、迁移和糖酵解，破坏 BHLHE40/GRIN2D 轴可能是 GC 的一种有吸引力的治疗策略。
