EXO1 overexpression is associated with poor prognosis of hepatocellular carcinoma patients
EXO1 overexpression is associated with poor prognosis of hepatocellular carcinoma patients
复制标题
EXO1过表达与肝细胞癌患者预后不良相关
DOI：
10.1080/15384101.2018.1534511
复制
发表时间：
2018-10-18
期刊：
影响因子：
4.3
通讯作者：
Zhu, Junfeng
中科院分区：
文献类型：
--
作者：
Dai, Yaoyao;Tang, Zuxiong;Zhu, Junfeng
外切核酸酶1(EXO1)在肝细胞癌(HCC)发生、发展中的作用尚不清楚。本研究旨在评估EXO1在肝细胞癌中的预后价值和治疗潜力。Exo1基因拷贝数取自3个肿瘤微阵列数据集(n=447)。半定量聚合酶链式反应和Quantigene(R)2.0检测Exo1基因的表达。用细胞生长曲线和集落形成法检测细胞增殖情况。采用克隆形成实验、流式细胞仪和免疫荧光等方法检测EXO1基因敲除和辐射对细胞存活、细胞周期分布和DNA修复的影响。Western blotting分析其相关机制。在已发表的三组不同的微阵列数据中，在肝癌标本中发现了Exo1基因的显著拷贝数变异(CNV)。在143例患者中，ExO1的表达水平升高(86.71%，124/143)。此外，ExO1过表达与肿瘤体积较大(P=0.002)、淋巴结转移增加(P=0.033)和Edmondson分级较低(P=0.018)有关。ExO1高表达对总生存期(OS)有不良影响(P=0.009)。单因素和多因素COX回归分析均显示EXO1是OS的独立预测因素(单变量，P=0.012；多变量，P=0.039)。在体外沉默EXO1可降低细胞增殖。Exo1基因敲除进一步抑制了克隆形成细胞的存活，消除了辐射诱导的G2/M期停滞，并增强了辐射后的伽马-H_2AX灶。突变型共济失调血管扩张症(ATM)的蓄积可能部分调节EXO1相关的放射敏感性。综上所述，EXO1可能是一个很有前途的预后标志物，在肝细胞癌中具有潜在的治疗价值。
The roles of exonuclease 1 (EXO1) in hepatocellular carcinoma (HCC) tumorigenesis and progression remain unclear. This study aimed to assess the prognostic value and therapeutic potential of EXO1 in HCC. Exo1 gene copy numbers were obtained from three Oncomine microarray datasets (n = 447). EXO1 mRNA expression was validated by semi-quantitative PCR and QuantiGene (R) 2.0 assays. Cell growth curve and colony formation were performed to asses the cell proliferation. Clonogenic assay, flow cytometry, and immunofluorescence were adopted to acess the effects of EXO1 knockdown and radiation on cell survival, cell cycle distribution and DNA repair. Western blots were performed to reveal the related mechanism. A significant copy number variation (CNV) of the Exo1 gene was found in HCC specimens in three separate sets of published microarray data. In the 143 cases treated by our team, EXO1 expression levels were elevated (86.71%, 124/143). In addition, EXO1 overexpression was correlated with larger tumor size (P = 0.002), increased lymph node metastasis (P=0.033) and lower Edmondson grade (P = 0.018). High EXO1 expression unfavorably affected overall survival (OS) (P = 0.009). Both univariate and multivariate Cox regression analyses identified EXO1 as an independent predictor of OS (univariate, P = 0.012; multivariate, P = 0.039). Silencing of EXO1 in vitro reduced cell proliferation. EXO1 knockdown further suppressed clonogenic cell survival, abrogated radiation-induced G2/M phase arrest, and enhanced gamma-H2AX foci after exposure to irradiation. The accumulation of ataxiatelangiectasia mutated (ATM) might partially regulate the EXO1 related radiosensitivity. In summary, EXO1 could be a promising prognostic marker, with a potential therapeutic value in HCC.