三磷酸腺苷酶家族蛋白2与β链蛋白在肝细胞癌中的表达及机制  

Expressions and mechanisms of ATPase family AAA domain-containing protein 2 and catenin in hepatocellnlar carcinoma

作　　者：孟祥宇 吴刚[2] 郑昆明[3] 夏书官 王雅玮[5] 程颖[2] Meng Xiangyu;Wu Gang;Zheng Kunming;Xia Shuguan;Wang Yawei;Cheng Ying(Department of Gastric Surgery, The Clinical Oncology Institute of China Medical University, Liaoning Cancer Hospital, Shenyang 110042, China)

机构地区：[1]中国医科大学肿瘤医院辽宁省肿瘤医院胃外科,沈阳110042 [2]中国医科大学附属第一医院肝胆外科暨器官移植科 [3]天津市人民医院普外科 [4]河南大学附属淮河医院甲状腺乳腺外科 [5]中国医科大学附属第一医院老年病综合外科

出　　处：《中华肝胆外科杂志》2018年第4期245-252,共8页Chinese Journal of Hepatobiliary Surgery

基　　金：辽宁省自然科学基金（2015020529）;沈阳市科技局人口与健康科技攻关专项（F19-139-9-25）;中国医科大学附属第一医院科学研究基金（FSFH1511）

摘　　要：目的研究三磷酸腺苷酶家族蛋白2（ATAD2）与β链蛋白（β-catenin）在肝细胞癌中的表达及其与患者临床病理表现的关系，分析两者的相关性以及不同表达状态下患者的预后情况，探讨ATAD2与β-catenin异常表达的相关机制。方法实时PCR检测在中国医科大学附属第一医院接受手术治疗的40例肝细胞癌患者癌组织中ATAD2与β-catenin表达情况，实时PCR及蛋白印迹（Westernblot）检测肝癌细胞系ATAD2、APC、β-catenin及wnt信号通路下游靶基因表达。免疫组化实验方法检测80例肝细胞癌患者癌组织及20例对应癌旁组织中相同部位ATAD2与β-catenin表达情况。Kaplan-Meier法计算累积生存率，COX比例风险模型分析预后不良因素。结果免疫组化结果显示：ATAD2与β-catenin在肝细胞癌组织中的表达率分别为65．0％和55．0％，高于对应癌旁组织的30．0％和25．0％，差异有统计学意义（P〈0．05）。分析显示ATAD2高表达与肿瘤大小（P〈0．05）、转移（P〈0．05）、血AFP含量（P〈0．05）及TNM分期（P〈0．05）相关；β-catenin异常表达与肿瘤转移（P〈0．05）相关。相关性分析结果显示：ATAD2与β-catenin表达呈正相关（Pearson相关系数为0．578，P〈0．01；R2=0．3607，Spearman相关系数为0．495）。此种相关性在除外SK-hepl细胞系的其余4株细胞系中均被发现。ATAD2基因敲除后，APC表达上调，β-catenin表达下调。单因素及多因素分析结果显示：ATAD2及β-catenin表达情况、肿瘤大小、转移、血AFP水平及TNM分期是影响肝细胞癌患者预后的危险因素。ATAD2及β-catenin表达状态、肿瘤转移情况及血AFP水平是影响肝细胞癌患者预后的独立危险因素，ATAD2与β-catenin共表达患者的预后差于两者单阳性表达和双阴性表达的患者（P〈0．05）。ATAD2基因敲除能抑制writ信号通路下游靶基因survivin、cyclinDl、c-myc及MMP7蛋白表达。结论ATAObjective To investigate the expressions of ATPase family AAA domain-containing protein 2 （ATAD2） and β-catenin, and to analyze their correlations with clinicopathological features and prog- nostic significance in patients with hepatocellular carcinoma （HCC）. Methods The HCC tissues of 40 patients were tested by real-time PCR to study the expressions of ATAD2 and β-eatenin. Real-time PCR and Western blot were performed to detect the proteins and mRNA levels of ATAD2, APC, β-catenin and wnt signaling pathway downstream. The HCC tissues of 80 patients and 20 peritumoral tissues were tested by immunohistochemistry （IHC）. The cumulative survival-rate was analyzed by the Kaplan-Meier method, and univariate and multivariate were analyzed by the Cox proportional hazards model. Results ISH： The posi- tive rates of ATAD2 and β-catenin were 65.0% and 55.0%, respectively. These rates were significantly higher than those in the peritumoral tissues （30. 0% and 25.0% , respectively）. The ATAD2 expression was related to tumor size （ P 〈 0.05 ）, metastasis （ P 〈 0.05 ）, serum AFP level （ P 〈 0.05 ） and TNM staging （P 〈 0.05 ）. The β-catenin expression was only significantly related to metastasis （ P 〈 0.05 ）. Correlation analysis showed that the ATAD2 expression was positively related to the β-catenin expression （ Pearson =0. 578, P 〈0.01, R2 =0.3607, Spearman =0. 495）. This positive relationship was also found in the remaining 4 cell lines except the SK-hepl. Depleting ATAD2 up-regulated APC and down-regulated β-catenin protein and mRNA expression. Univariate and multivariate analyses showed that ATAD2 and β-catenin expressions, tumor size, metastasis, serum AFP, and TNM staging were poor prognostic factors for HCC, and ATAD2 and β-catenin expressions, metastasis, serum. AFP were independent prognostic factors. Patients whose ATAD2 and β-catenin were both positive had worse survival than those with only one positive expres- sion or both negative expressions （ P �

关 键 词：癌 肝细胞 三磷酸腺苷酶家族蛋白2 β链蛋白 信号传导 

分 类 号：R735.7[医药卫生—肿瘤]