食管鳞状细胞癌放化疗敏感性关键基因的鉴定  

Identification of key genes in response to radiotherapy and chemotherapy in esophageal squamous cell carcinoma based on multiple datasets

作　　者：张耀文[1] 刘昀松 惠周光 曹莎莎 汪晨宇 程欣宇 金琳芝 任润川 Zhang Yaowen;Liu Yunsong;Hui Zhouguang;Cao Shasha;Wang Chenyu;Cheng Xinyu;Jin Linzhi;Ren Runchuan(Department of Radiation Oncology,Anyang Tumor Hospital,The Affiliated Anyang Tumor Hospital of Henan University of Science and Technology,Henan Medical Key Laboratory of Precise Prevention and Treatment of Esophageal Cancer,Anyang 455000,China;Special Medical Services Department,National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100021,China)

机构地区：[1]安阳市肿瘤医院放疗科,河南科技大学附属安阳市肿瘤医院,河南省食管癌精准防治医学重点实验室,安阳455000 [2]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特需医疗部,北京100021

出　　处：《中华放射肿瘤学杂志》2024年第10期950-957,共8页Chinese Journal of Radiation Oncology

基　　金：河南省中青年卫健委科技创新杰青人才项目(YXKC2021045);河南省科技攻关项目(212102310702);安阳市科技攻关项目(2021C01SF011);中国癌症基金会北京希望马拉松专项基金(LC2022R03)。

摘　　要：目的:探究食管鳞状细胞癌(ESCC)放化疗敏感性相关生物标志物及其潜在机制,并在人体组织、动物和细胞水平验证。方法:基于生物信息学系统,从癌症基因组图谱(TCGA)数据库、GEO数据库获取ESCC的临床和转录组数据。通过加权基因共表达网络分析(WGCNA)与cytoscape软件鉴定放化疗敏感性相关HUB基因并进行生存差异分析。通过CellMiner数据库预测筛选与HUB基因具有较强相关性的药物。利用实时反转录聚合酶链式反应(qRT-PCR)检测ESCC患者组织中HUB基因的表达水平。构建醛酮还原酶家族1成员C1(AKR1C1)高表达的oe-AKR1C1小鼠模型,以及顺铂耐药细胞和放射抵抗细胞,分析HUB基因对肿瘤体积和质量、细胞增殖能力的影响。结果:共筛选到5个HUB基因,其中醌脱氢酶(NQO1)、AKR1C1和NADH:泛醌氧化还原酶核心亚基S2(NDUFS2)与ESCC的生存显著相关(P<0.05)。达卡巴嗪、alectinib和obatoclax等是本研究预测的与HUB基因具有较强相关性的抗肿瘤药物。人体组织检测结果显示,NQO1、AKR1 C1和NDUFS2的表达水平在放化疗耐药患者中显示为上调,其中AKR1C1和NDUFS2具有统计学意义(P<0.05)。小鼠荷瘤实验结果显示,oe-AKR1C1小鼠在放疗和化疗后的肿瘤体积和质量均显著高于对照组(P<0.05)。细胞实验结果发现,放射抵抗细胞和顺铂耐药细胞的AKR1C1和NDUFS2的表达水平均显著高于对照细胞(P<0.05),而NQO1相对表达量的差异无统计学意义。结论:NQO1、AKR1C1和NDUFS2是与ESCC生存显著相关的HUB基因,可作为ESCC治疗的重要肿瘤靶点。ObjectiveTo explore the biomarkers of radiochemotherapy sensitivity and potential mechanisms in esophageal squamous cell carcinoma(ESCC),and validate the screened biomarkers at human tissue,animal and cellular levels.MethodsBased on bioinformatics system,clinical and transcriptome data of ESCC were obtained from The Cancer Genome Atlas(TCGA)and GEO databases.HUB genes related to chemoradiotherapy sensitivity were identified by weighted correlation network analysis(WGCNA)and cytoscape software and survival differences were analyzed.CellMiner database was used to predict and screen drugs with strong correlation with HUB genes.The expression levels of HUB genes in clinical tissues was detected by real-time reverse transcription PCR(qRT-PCR).Then,oe-AKR1C1 mouse model,cisplatin-resistant cells and radiation-resistant cells were constructed,and the effects of HUB genes on tumor size and mass,and cell proliferation ability were analyzed.ResultsA total of 5 HUB genes were identified,among which NAD(P)H quinone dehydrogenase 1(NQO1),AKR1C1 and NADH:ubiquinone oxidoreductase core subunit S2(NDUFS2)were significantly correlated with ESCC survival(all P<0.05).Dacarbazine,alectinib and obatoclax were the anti-tumor drugs predicted to have a strong correlation with HUB genes in this study.Human tissue test results showed that the expression levels of NQO1,AKR1C1 and NDUFS2 were up-regulated in patients with chemoradiotherapy resistance,and AKR1C1 and NDUFS2 had statistical significance(both P<0.05).The results of mouse tumor bearing experiment showed that the tumor volume and mass of oe-AKR1C1 mice after radiotherapy and chemotherapy were significantly higher than those in the control group(both P<0.05).The cell experiment results showed that the expression levels of AKR1C1 and NDUFS2 in radiation-resistant cells and cisplatin-resistant cells were significantly higher than those in control cells(P<0.05),while there was no statistically significant difference in the relative expression level of NQO1.Conclusion NQO1,AKR1C1 and

关 键 词：食管鳞状细胞癌 放化疗法 加权基因共表达网络分析 HUB基因 竞争性内源RNA网络 

分 类 号：R735.1[医药卫生—肿瘤]