网站首页杂志简介编委会成员过刊目录投稿指南在线订阅联系我们读者论坛Mil Med Res
消息通知:

 

位置:首页 >> 在线订阅
食管癌化疗耐药相关基因的初步筛选及其临床意义
作者:南鹏 李春晓 孙芳洲 窦娜 郭建宾 王海娟 
单位:100021  北京 国家癌症中心/国家肿瘤临床医学研究中心/中国医学科学院北京协和医学院肿瘤医院分子肿瘤学国家重点实验室(南鹏、李春晓、孙芳洲、窦娜、郭建宾、王海娟) 
关键词:食管癌 耐药 受体蛋白酪氨酸激酶信号通路 FGR基因 
分类号:R735.1
出版年,卷(期):页码:2019,44(3):222-227
摘要:

 [摘要]  目的  初步筛选食管癌细胞中的耐药相关基因,分析其与食管癌患者预后不良的相关性,探讨其调控食管癌耐药的潜在机制。方法  分析GDSC数据库中收录的食管癌细胞系对药物敏感性的数据,筛选出同时对顺铂和多西他赛相对敏感或耐药的细胞系;借助R语言edgeR软件包,以log2(变化倍数)大于1或小于–1P<0.05为筛选标准,对两组细胞系转录组数据进行差异表达基因分析;选择在耐药组中相对高表达的基因进行GO生物学过程富集聚类分析,了解其可能调控的与耐药相关的信号通路;结合文献报道,获得新的可能与化疗耐药相关的基因。在食管癌患者肿瘤组织的转录组数据中分析所获得的基因的表达水平与患者临床病理特征及预后的相关性,最终通过STRING数据库在线预测与筛选获得的基因表达产物互作的蛋白,分析其发挥作用的潜在机制。结果  初步筛选获得同时对顺铂和多西他赛相对耐药和敏感的食管癌细胞系各5株;分析耐药和敏感两组细胞系的转录组数据,最终共筛选获得1097 个差异表达基因,包括在耐药组中高表达的基因532个、低表达的基因565个。将耐药组高表达的基因进行GO富集分析,发现受体蛋白酪氨酸激酶通路被显著富集,该通路中的差异表达基因FGR的表达水平与临床食管癌患者肿瘤T分期(P=0.021)、临床分期(P=0.007)及预后(P=0.0021)显著相关。蛋白相互作用分析表明,FGR与多个蛋白直接或间接互作,FGR可能主要以激酶的形式发挥作用。结论  受体蛋白酪氨酸激酶通路与食管癌细胞耐药显著相关,该信号通路中的FGR基因表达水平与食管癌患者的临床病理分期及预后显著相关,其可能通过磷酸化下游靶蛋白进而调控食管癌细胞的耐药。

 [Abstract]  Objective  To initially screen the genes associated with chemotherapeutic resistance in esophageal cancer cells, verify the correlation of the genes to the poor prognosis of patients with esophageal cancer, and predict the possible regulatory mechanism of esophageal cancer resistance. Methods  The drug sensitivity data of esophageal cancer cell lines were analyzed from GDSC database to screen the cell lines that were relatively sensitive or resistant to both cisplatin and docetaxel. In order to obtain differentially expressed genes, the transcriptome data of the two groups of cell lines were analyzed by the edgeR package according to the following screening criteria: the log2 (fold change) more than –1 or less than1 and P value <0.05. The enrichment cluster analysis of GO biological process was performed in the relatively highly expressed genes of drug-resistant group to identify possible signaling pathways related with drug resistance, and the target genes related to chemotherapeutic resistance were identified based on previous studies. The associations between the expression level of target gene and the clinical pathological features and prognosis of patients were verified in the tissue transcriptome data of esophageal cancer patients. Finally, the proteins interacting with the target gene encoded protein were predicted online using the STRING database, and its possible mechanism of action was analyzed. Results  Five cell lines with resistance to both cisplatin and docetaxel and 5 sensitive cell lines were obtained. According to the transcriptome data of the two groups of cell lines, 1097 differentially expressed genes were finally obtained, including 532 highly expressed and 565 low expressed genes in the drug resistant group. The results of GO enrichment analysis for the highly expressed genes indicated that the receptor protein tyrosine kinase pathway was obviously enriched. The expression level of FGR involved in this pathway was significantly correlated with tumor T stage (P=0.021), clinical stage (P=0.007) and prognosis (P=0.0021) of patients with esophageal cancer. In addition, protein interaction analysis indicated that FGR interacted directly or indirectly with multiple proteins, mainly in the form of kinase. Conclusions  The receptor protein tyrosine kinase pathway is the most significant signaling pathway associated with chemotherapeutic resistance in esophageal cancer cells. The expression level of FGR in this signaling pathway is significantly correlated with the pathological stage and prognosis of patients with esophageal cancer. FGR may regulate the drug resistance of esophageal cancer cells by phosphorylating downstream target proteins.

基金项目:
国家自然科学基金(81672459,81872280)
作者简介:
参考文献:
服务与反馈:
文章下载】【加入收藏

copyright ©《解放军医学杂志》编辑部
地址:北京市海淀区复兴路22号甲3号人民军医出版社   邮编:100036
电话:0201-882929-8021(军线)    010-51927306 (传真)
京ICP备06014771-2