摘要
脱氧尿苷三磷酸核苷酸水解酶(deoxyuridine 5’-triphosphate nucleotidohydrolase,dUTPase)是由DUT基因编码的DNA合成过程中的关键酶。研究显示其在维护基因组稳定性过程中充当基因组管家的作用,而其在胃癌中的表达及作用尚不清楚。该研究首先利用iTRAQ标记的定量蛋白组学从胃癌组织样本中鉴定出dUTPase高表达,经TIMER数据库分析得出dUTPase在胃癌中高表达,并经实时荧光定量PCR(quantitative real-time PCR,qPCR)及免疫组化(immunohistochemistry,IHC)等方法检测显示,dUTPase在胃癌组织中显著高表达,且其表达与组织学分级及TNM分期等临床病理因素相关。预后分析结果显示:dUTPase高表达与胃癌患者的首次进展生存期(first progression survival,FP)、总生存期(overall survival,OS)、复发后生存期(post progression survival,PPS)及HER2阳性状态显著相关。基因富集分析(gene set enrichments analysis,GSEA)结果显示:DUT高表达胃癌患者中有185条信号通路显著被激活,涉及DNA合成、DNA修复及基因组稳定性等多个方面。一系列体外功能实验结果显示,体外抑制DUT基因表达可显著抑制胃癌细胞的增殖及体外迁移。总之,该研究证实了dUTPase在胃癌中显著高表达,其表达可能与多条参与DNA合成、修复及基因组稳定性的肿瘤信号通路相关,靶向dUTPase可显著抑制胃癌细胞的增殖及迁移。
dUTPase (deoxyuridine 5’-triphosphate nucleotidohydrolase) encoded by DUT gene is a key enzyme in the DNA synthesis process.Recent studies have shown that it acts as a “House keeper” in the protection of genome stability,but its expression and roles in gastric cancer are still unclear.In this study,iTRAQ-labeled quantitative proteomics was used to identify the high expression of dUTPase in gastric cancer tissue samples.TIMER database analysis confirmed that dUTPase was highly expressed in gastric cancer.The results of qPCR (quantitative real-time PCR) and IHC (immunohistochemistry) showed that the expression of dUTPase was significantly higher in gastric cancer tissues,its expression was correlated with clinicopathological factors such as histological grade and TNM stages.Prognostic analysis showed that high expression of dUTPase was associated with FP (first progression survival),OS (overall survival),PPS (post progression survival) and HER2 positive status.GSEA (gene set enrichment analysis) showed that 185 signaling pathways were significantly activated in gastric cancer patients with high expression of DUT,involving DNA synthesis,DNA repair and genome stability.A series of in vitro functional experiments showed that inhibition of DUT gene expression in vitro could significantly inhibit the proliferation and the migration of gastric cancer cells.In conclusion,this study confirmed that dUTPase was significantly overexpressed in gastric cancer,and its expression might activate multiple tumor signaling pathways involved in DNA synthesis,DNA repair,and genomic stability.Targeting dUTPase can significantly inhibit the proliferation and migration of gastric cancer cells.
作者
蒋振
谢杰斌
肖杨
罗瑶敏
魏晨
袁晓霞
JIANG Zhen;XIE Jiebin;XIAO Yang;LUO Yaomin;WEI Chen;YUAN Xiaoxia(Institute of Basic Medicine and Forensic Medicine,North Sichuan Medical College,Nanchong 637100,China;Department of Biochemistry and Molecular Biology,School of Basic Medicine and Forensic Medicine,North Sichuan Medical College,Nanchong 637100,China;Department of Gastrointestinal Surgery,Affiliated Hospital of North Sichuan Medical College,Nanchong 637100,China;School of Pharmacy,North Sichuan Medical College,Nanchong 637100,China)
出处
《中国细胞生物学学报》
CAS
CSCD
2022年第10期1885-1895,共11页
Chinese Journal of Cell Biology
基金
国家自然科学基金(批准号:81702093)
四川省科学技术厅(批准号:2020YJ0379)
南充市市校合作项目(批准号:20SXJCQN0004、20SXQT0053、18SXHZ0281)资助的课题。
