ONECUT2高表达介导胃癌复发患者5-FU化疗耐药  

High expression of ONECUT2 mediates 5-FU chemotherapy resistance in patients with recurrent gastric cancer

作　　者：朱海峰[1] 陈述[2] 龙卫国[3] 王旭[4] ZHU Haifeng;CHEN Shu;LONG Weiguo;WANG Xu(Department of Chemotherapy,Affiliated Hospital of Jiangsu University,Zhenjiang Jiangsu 212001,China;Department of Hepatobiliary Surgery,Affiliated Hospital of Jiangsu University,Zhenjiang Jiangsu 212001,China;Department of Pathology,Affiliated Hospital of Jiangsu University,Zhenjiang Jiangsu 212001,China;Department of Radiation Oncology,Affiliated Hospital of Jiangsu University,Zhenjiang Jiangsu 212001,China)

机构地区：[1]江苏大学附属医院化疗科,江苏镇江212001 [2]江苏大学附属医院肝胆外科,江苏镇江212001 [3]江苏大学附属医院病理科,江苏镇江212001 [4]江苏大学附属医院放疗科,江苏镇江212001

出　　处：《江苏大学学报（医学版）》2024年第1期19-24,共6页Journal of Jiangsu University：Medicine Edition

基　　金：江苏省自然科学基金面上项目(BK20211124)。

摘　　要：目的:探究One cut结构域家族成员2(ONECUT2)是否可以作为对5-FU耐药的胃癌复发患者的治疗靶点。方法:利用癌症基因组图谱(TCGA)数据库分析ONECUT2基因在胃癌患者及胃癌复发患者的表达情况。利用基因集富集分析(GSEA)评估TCGA数据库中ONECUT2表达量与药物代谢相关生物学过程的相关性。利用CCK-8细胞毒性实验评估胃癌细胞敲低或过表达ONECUT2对5-FU的耐药情况。分析30例胃癌术后复发患者ONECUT2表达量与5-FU治疗效果的相关性。结果:TCGA数据库分析显示,在经受过化疗且复发的胃癌患者中,ONECUT2高表达的患者无病间隔期(disease-free interval,DFI)更短。GSEA分析结果表明,ONECUT2高表达与异生药物代谢通路呈正相关,这提示可能与胃癌患者的耐药相关。体外实验中,敲低ONECUT2降低胃癌细胞对5-FU的半数抑制浓度(IC_(50))值;反之,过表达ONECUT2增加细胞对5-FU的IC_(50)值。30例胃癌复发患者对5-FU的药物敏感性与ONECUT2表达量相关。结论:胃癌复发患者的ONECUT2表达量更高,ONECUT2高表达与胃癌复发患者的5-FU耐药相关,可能是潜在的治疗靶点。Objective:To explore whether one cut domain family member 2(ONECUT2)transcription factor could be a therapeutic target for 5-FU resistant gastric cancer(GC)relapsed patients.Methods:The Cancer Genome Atlas(TCGA)database was used to analyze the expression level of ONECUT2 in GC patients and GC relapsed patients.Gene set enrichment analyses(GSEA)were performed using STAD patients from TCGA to explore the correlation between ONECUT2 and biological processes related to drug metabolism.CCK-8 cytotoxic assays were performed to evaluate the role of ONECUT2 knockdown or overexpression on 5-FU resistance in gastric cancer cell lines.30 relapsed GC patients with previously resected tumor samples were recruited to analyze the correlation between ONECUT2 expression level and 5-FU treatment efficacy.Results:According to the results of TCGA data analysis,in GC patients with chemotherapeutic treatment and cancer reoccurrence events,higher ONECUT2 level contributed to shorter disease-free interval.GSEA results suggested that upregulated ONECUT2 was positively correlated with xenobiotic drug metabolism,and which was related to drug resistance in GC patients.ONECUT2 knockdown reduced IC_(50)value of 5-FU in GC cells in vitro;on the contrast,ONECUT2 overexpression increased IC_(50)value of 5-FU in GC cells in vitro.The sensitivity of 5-FU treatment was negatively correlated with ONECUT2 mRNA level of tumor samples derived from 30 GC patients who relapsed after surgical resection.Conclusion:Relapsed GC patients had a higher expression of ONECUT2,and higher ONECUT2 expression level was positively related to 5-FU resistance in relapsed GC patients.These results provided a potential therapeutic target for GC treatment.

关 键 词：One cut结构域家族成员2 胃癌复发 5-FU耐药 GSEA 细胞毒性 半数抑制浓度 

分 类 号：R735.2[医药卫生—肿瘤]