Chen Wenchao, Yang Fanfan, Shen Hao, Xu Jia, Chen Jin, Zhang Zhezhong, Xu Jian, Xu Bin
Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
School of Medical Technology and Information Engineering, Zhejiang Chinese Medical University, Hangzhou, China.
Transl Cancer Res. 2024 Aug 31;13(8):4459-4473. doi: 10.21037/tcr-23-2222. Epub 2024 Aug 23.
Gastric cancer (GC) is a gastric malignant tumor with over 1 million new cases globally each year. There are many diagnostic methods for GC, but due to the hidden early symptoms of GC, early GC is easy to be missed and misdiagnosed, which affects the follow-up treatment of patients. The early and accurate diagnosis of GC is of great significance for the treatment and survival of GC patients. Our laboratory study found that gamma-glutamyl transferase (GGT) was highly expressed in GC patients, but the mechanism of GGT family genes in the occurrence and development of GC remained to be further studied. Therefore, this study aimed to explore the mechanism of GGT family functional gene GGT5 regulating the proliferation and migration of GC cells, and provide a possible new biomarker for the early diagnosis of GC.
The value of serum GGT in GC patients was first statistically analyzed. Then, The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets were used to analyze the mRNA expression of GGT5 in GC, and its clinical relationship and function. Furthermore, expression of GGT5 was reduced by lentivirus RNA interference and verified by polymerase chain reaction (PCR), Cell Counting Kit-8 (CCK-8) and 5-ethynyl-2'-deoxyuridine (EdU) assays were used to detect cell proliferation after GGT5 knockdown. Scratch and Transwell assays were applied to observe cell migration after knockdown of GGT5. Finally, Western blot assays were observed to demonstrate PI3K/AKT-MAPK and MMPs expression levels after knockdown of GGT5.
Serum GGT was expressed at a high level in GC patients. GGT5 was highly expressed in GC tissues, and was associated with poor prognosis and clinical stage of GC. GGT5 might be involved in the regulation of vascular development and angiogenesis, as well as in the mechanisms of cell motility and migration, and it was positively correlated with the PI3K/AKT pathway. The proliferation and migration capacity of GC cells was dampened by downregulation of GGT5. GGT5 mediated proliferation and migration of GC cells by directly targeting PI3K/AKT-MAPK-MMPs pathways.
Low expression of GGT5 reduced proliferation and migration in GC cells by modulating the PI3K/AKT-MAPK-MMPs pathway, and GGT5 might be a new target for GC.
胃癌（GC）是一种胃部恶性肿瘤，全球每年新增病例超过100万。胃癌有多种诊断方法，但由于胃癌早期症状隐匿，早期胃癌容易被漏诊和误诊，影响患者的后续治疗。胃癌的早期准确诊断对胃癌患者的治疗和生存具有重要意义。我们的实验室研究发现，γ-谷氨酰转移酶（GGT）在胃癌患者中高表达，但GGT家族基因在胃癌发生发展中的作用机制仍有待进一步研究。因此，本研究旨在探讨GGT家族功能基因GGT5调控胃癌细胞增殖和迁移的机制，为胃癌的早期诊断提供一种可能的新生物标志物。
首先对胃癌患者血清GGT值进行统计学分析。然后，利用癌症基因组图谱（TCGA）和基因表达综合数据库（GEO）分析GGT5在胃癌中的mRNA表达及其临床关系和功能。此外，通过慢病毒RNA干扰降低GGT5表达，并通过聚合酶链反应（PCR）进行验证，采用细胞计数试剂盒-8（CCK-8）和5-乙炔基-2'-脱氧尿苷（EdU）检测GGT5敲低后细胞的增殖情况。划痕实验和Transwell实验用于观察GGT5敲低后细胞的迁移情况。最后，通过蛋白质免疫印迹实验观察GGT5敲低后PI3K/AKT-MAPK和基质金属蛋白酶（MMPs）的表达水平。
胃癌患者血清GGT高水平表达。GGT5在胃癌组织中高表达，与胃癌的不良预后和临床分期相关。GGT5可能参与血管发育和血管生成的调控，以及细胞运动和迁移机制，且与PI3K/AKT通路呈正相关。下调GGT5可抑制胃癌细胞的增殖和迁移能力。GGT5通过直接靶向PI3K/AKT-MAPK-MMPs通路介导胃癌细胞的增殖和迁移。
GGT5低表达通过调节PI3K/AKT-MAPK-MMPs通路降低胃癌细胞的增殖和迁移，GGT5可能是胃癌的一个新靶点。
