σ1受体在子宫颈癌组织中高表达的意义及其配体化合物对子宫颈癌细胞生长的作用  

Clinical significance of σ1 receptor over-expression in cervical cancer and the effect of its synthetic ligands on the growth of cervical cancer cells

作　　者：邓亚勤 周新欢[3] 姜李乐[1] 唐相靖 张运晓[2] 崔金全[1] 

机构地区：[1]郑州大学第二附属医院妇产科,450014 [2]郑州大学化学与分子工程学院,450014 [3]河南省南阳市中心医院妇科

出　　处：《中华妇产科杂志》2017年第7期473-482,共10页Chinese Journal of Obstetrics and Gynecology

基　　金：河南省医学科技攻关计划（201201010）

摘　　要：目的探讨σ1受体（σ1R）在子宫颈癌组织中高表达的意义及其配体化合物对子宫颈癌细胞生长的作用。方法（1）收集2007年1月至2012年12月郑州大学第二附属医院病理科存档的经手术切除或活检的不同程度子宫颈病变组织蜡块160份，其中子宫颈癌组织88份、高级别鳞状上皮内病变（HSIL）组织42份、正常子宫颈组织30份（因子宫肌瘤、单纯良性卵巢囊肿行子宫全切除术）；另选择HPV18型阳性的子宫颈腺癌细胞系HeLa细胞和HPV16型阳性的子宫颈鳞癌细胞系SiHa细胞。采用免疫组化SP法检测上述组织和细胞中σ1R蛋白的表达，并分析σ1R蛋白表达与子宫颈癌患者不同临床病理特征及预后的相关性。（2）从癌症基因组图谱（TCGA）数据库中筛选出临床资料和σ1R基因数据均完整的子宫颈癌患者249例，分析σ1R表达与子宫颈癌患者不同临床病理特征的相关性。（3）合成σ1R配体化合物（共4个，分别为化合物14a、14e、15c、15f）并作用于HeLa、SiHa细胞，采用四甲基偶氮唑蓝（MTT）比色法检测细胞增殖情况及细胞对奈达铂的敏感性，细胞划痕实验检测细胞迁移能力，流式细胞仪检测细胞周期比例和凋亡率。结果（1）免疫组化SP法检测显示，正常子宫颈组织中σ1R蛋白少量表达于胞质，HSIL组织中σ1R蛋白中等量表达于胞质及个别胞核，子宫颈癌组织中σ1R蛋白大量表达于胞质和胞核；子宫颈癌HeLa和SiHa细胞中σ1R蛋白大量表达于胞质和胞核。子宫颈癌患者σ1R蛋白的阳性表达率与病理类型明显相关（P=0.020），而与患者年龄、临床分期、病理分化程度均无明显相关性（P〉0.05）。子宫颈腺癌患者σ1R蛋白的胞核表达阳性率（10/18）明显高于子宫颈鳞癌（27.1%，19/70；P=0.024）。70例子宫颈鳞癌患者中，47例σ1R蛋白阳性患者的中位生存时间[（45.8±3.1）个月]明显低于23例σ1R蛋白阴ObjectiveTo explore the role of σ1 receptor （σ1R） in the clinical prognosis of cervical cancer,and provide a theoretical basis for σ1R targeted molecular therapy through observing the inhibition of synthetic σ1R-specific ligand compounds on the growth of cervical cancer cells. Methods（1） Immunohistochemical or immunocytochemistry staining were respectively used to detect the expression and localization of σ1R protein. （2） The Cancer Genome Atlas （TCGA） data set was used to validate our results. （3） Two series of 4 novel σ1R ligand compounds were synthesized by altering the N-terminal substituents on the piperidine ring of the prezamicol analogue, named as 14a, 14e, 15c and 15f. Methyl thiazolyl-tetrazolium （MTT） assay was detect the anti-proliferative effect of the four compounds on HeLa and SiHa cells. Compound 14a with potent inhibitory activity and the highest specificity of σ1R was selected for further experiments. Scratch test was observed the migration effect of compound 14a on HeLa and SiHa cells. Flow cytometry was determined cell cycles and apoptosis.Results（1） Immunostaining of σ1R protein was located in the cytoplasm and nucleus of cervical epithelium. The expression of cervical squamous cell carcinoma （SCC） was significantly higher than those of high-grade squamous intraepithelial lesion （HSIL） or normal cervical tissues. There was no significant difference in the expression of σ1R between HSIL and normal cervical tissues. σ1R expression in cervical adenocarcinoma （AC） was higher than that in SCC （P=0.020）. The nuclear expression rate of σ1R in AC （10/18） was higher than that of SCC （27.1%, 19/70; P=0.024）. The median overall survival （MOS） of σ1R-positive SCC patients was lower than that of σ1R-negative patients [（45.8±3.1） vs （51.7±2.9） months, P=0.045]. MOS of the patients with σ1R nuclear positive SCC was lower than that of non-nuclear staining [（38.9±3.8） vs （48.7±2.1） months, P=0.022]. MOS of the patient

关 键 词：宫颈肿瘤 HELA细胞 细胞系 肿瘤 受体 ∑ 哌啶类 

分 类 号：R737.33[医药卫生—肿瘤]