EYA4基因作为一种预后标志物发挥作用，并抑制肝内胆管癌的生长。
EYA4 gene functions as a prognostic marker and inhibits the growth of intrahepatic cholangiocarcinoma.
作者信息
Hao Xiao-Yi, Cai Jian-Peng, Liu Xin, Chen Wei, Hou Xun, Chen Dong, Lai Jia-Ming, Liang Li-Jian, Yin Xiao-Yu
机构信息
Departments of Pancreatobiliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Zhongshan 2nd Road, Guangzhou, 510080, Guangdong, P. R. China.
出版信息
Chin J Cancer. 2016 Jul 28;35(1):70. doi: 10.1186/s40880-016-0133-z.
BACKGROUND
The molecular prognostic markers and carcinogenesis of intrahepatic cholangiocarcinoma (ICC) have not been well documented. The purpose of this study was to investigate the prognostic value of the eyes absent homolog 4 (EYA4) gene in ICC and its biological effects on ICC growth in vitro and in vivo.
METHODS
One hundred twelve patients with ICC who underwent hepatectomy were enrolled in the study. EYA4 mRNA and EYA4 protein levels in ICC and adjacent non-tumoral tissues were evaluated using real-time quantitative polymerase chain reaction and immunohistochemical staining, respectively. EYA4 protein levels in ICC cells were determined using western blot analysis. The associations between EYA4 expression and clinicopathologic features of ICC were analyzed. To identify independent prognostic factors, univariate and multivariate analyses were performed. The biological effects of EYA4 on ICC cells were evaluated by establishing stable EYA4-overexpressing transfectants in vitro, and EYA4's effects on tumor growth were evaluated by intra-tumoral injection of EYA4-expressing plasmids in a NOD/SCID murine model of xenograft tumors.
RESULTS
ICC tissues had significantly lower EYA4 mRNA and protein levels compared with adjacent non-tumoral tissues (both P < 0.001). Univariate and multivariate analyses showed that EYA4 protein level, tumor number, adjacent organ invasion, lymph node metastasis, and tumor differentiation were independent prognostic factors for disease-free survival and overall survival (all P < 0.05). In vitro, EYA4 overexpression inhibited tumor cell growth, foci formation, and cell invasiveness. In vivo, intra-tumoral injection of EYA4-expressing plasmids significantly inhibited ICC growth in the murine xenograft model compared with the control group (P < 0.05).
CONCLUSION
EYA4 gene functioned as a molecular prognostic marker in ICC, and its overexpression inhibited tumor growth in vitro and in vivo.
背景
肝内胆管癌（ICC）的分子预后标志物和致癌机制尚未得到充分记录。本研究的目的是探讨无眼同源物4（EYA4）基因在ICC中的预后价值及其对ICC体外和体内生长的生物学影响。
方法
112例行肝切除术的ICC患者纳入本研究。分别采用实时定量聚合酶链反应和免疫组织化学染色评估ICC及癌旁非肿瘤组织中EYA4 mRNA和EYA4蛋白水平。采用蛋白质免疫印迹分析测定ICC细胞中EYA4蛋白水平。分析EYA4表达与ICC临床病理特征之间的关系。为确定独立预后因素，进行单因素和多因素分析。通过体外建立稳定过表达EYA4的转染细胞株评估EYA4对ICC细胞的生物学影响，并通过在NOD/SCID小鼠异种移植瘤模型中瘤内注射表达EYA4的质粒评估EYA4对肿瘤生长的影响。
结果
与癌旁非肿瘤组织相比，ICC组织中EYA4 mRNA和蛋白水平显著降低（均P < 0.001）。单因素和多因素分析显示，EYA4蛋白水平、肿瘤数量、邻近器官侵犯、淋巴结转移和肿瘤分化是无病生存期和总生存期的独立预后因素（均P < 0.05）。在体外，EYA4过表达抑制肿瘤细胞生长、集落形成和细胞侵袭性。在体内，与对照组相比，在小鼠异种移植模型中瘤内注射表达EYA4的质粒显著抑制ICC生长（P < 0.05）。
结论
EYA4基因在ICC中作为分子预后标志物发挥作用, 其过表达在体外及体内均抑制肿瘤生长。
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