基于细胞系和类器官研究c-Myc在肝癌治疗和耐药中的作用
Research on the role of c-Myc in liver cancer therapy and drug resistance using cell line and organoid models
程景辉 1秦艺萱 1杨慧1
作者信息
- 1. 北京大学第一医院肿瘤转化研究中心(北京市 100034)
- 折叠
摘要
目的:基于肝癌细胞系与类器官的药物基因组学数据探讨骨髓细胞瘤癌基因(c-Myc)的潜在治疗效果.方法:收集肝癌细胞系的药敏、功能基因组和基因表达数据,评估c-Myc的表达与药敏的关联.统计c-Myc表达在肝癌测序队列中的差异和预后相关性.免疫组织化学染色验证c-Myc在肝癌患者的表达,检测其与类器官生物库类器官的药敏关联.选取三种不同的c-Myc抑制剂在肝癌细胞系和类器官上进行药物筛选,检测干预c-Myc对二维、三维水平的肿瘤杀伤作用.生物信息学分析探究c-Myc与靶向耐药的相关性.结果:生物信息学分析联合免疫组织化学鉴定c-Myc在肝癌中调控药敏的潜在作用.c-Myc在癌组织中的表达明显高于癌旁组织,而且c-Myc的表达在靶向药耐药患者中高于靶向药敏感患者(P<0.05).药敏实验揭示了c-Myc抑制剂THZ1、ABBV-744、JQ1可杀伤肿瘤细胞及类器官,并且与仑伐替尼在细胞系SNU-739中显示出显著的协同致死作用(协同系数均>1).进一步的类器官生物库数据分析显示,c-Myc与干性介导的靶向耐药显著正相关(R=0.87).结论:c-Myc在在靶向治疗耐药患者中高表达,并且抑制c-Myc可在二维、三维体外模型中起到很好的肿瘤杀伤效果,肝癌中可作为一个新的靶点.
Abstract
To investigate the potential therapeutic effects of the myelocytomatosis oncogene(c-Myc)using pharmacogenomic data from liv-er cancer cell lines and organoids.Methods:Drug sensitivity,functional genomics,and gene expression data from cell lines were collected to assess the correlation between the expression of c-Myc and drug sensitivity.Differential expression and prognostic relevance of c-Myc in a primary liver cancer cohort were analyzed.Immunohistochemistry(IHC)staining validated c-Myc expression in liver cancer patients and cor-related it with the drug sensitivity of organoids obtained from an organoid biobank.Three c-Myc inhibitors were screened on liver cancer cell lines and organoids to test tumor-killing effects in two-and three-dimensional levels.Bioinformatics analysis was conducted to explore the role of c-Myc in targeted drug resistance.Results:Bioinformatics analyses combined with IHC staining revealed a potential regulatory role of c-Myc in the drug sensitivity of liver cancer.The expression of c-Myc in cancerous tissues was significantly higher than in para-cancerous tis-sues,and c-Myc expression was higher in patients resistant to targeted drugs than in those sensitive to targeted drugs(P<0.05).Drug screening experiments showed that c-Myc inhibitors including THZ1,ABBV-744,and JQ1 reduced cell viability in both tumor cells and tumor organoids.The combination of lenvatinib and c-Myc inhibitors exhibited significant synergistic effects(all synergy scores>1)in the SNU-739 cell line.Analysis of organoids from an organoid biobank indicated a strong association between c-Myc and stemness-mediated targeted drug resistance(R=0.87).Conclusions:c-Myc showed increased expression in patients resistant to targeted therapy,suggesting it as a novel target for drugs in liver cancer.Inhibition of c-Myc effectively killed tumors in both two-and three-dimensional ex vivo models.
关键词
肝癌/c-Myc/耐药性Key words
liver cancer/c-Myc/drug resistance引用本文复制引用
出版年
2024
NETL
NSTL
万方数据