摘要
目的:研究受体酪氨酸激酶(RON)蛋白与CXC趋化因子受体4(CXCR4)蛋白的表达与去势抵抗型前列腺癌(CRPC)患者阿比特龙耐药的相关性。方法:选取2017年1月至2020年2月我院收治的127例接受阿比特龙治疗的CRPC患者,根据是否耐药分为观察组(n=32,阿比特龙耐药患者)、对照组(n=95,缓解患者)。采用免疫组化与蛋白免疫印迹检测比较两组RON、CXCR4蛋白表达,采用Logistic回归分析进行RON、CXCR4蛋白与耐药的单因素、多因素分析,采用受试者工作特征曲线(ROC)及ROC下面积(AUC)分析RON、CXCR4蛋白预测耐药的价值,并在阿比特龙耐药细胞株中加入RON、CXCR4抑制剂,观察两者对阿比特龙耐药细胞凋亡指标[半胱氨酸蛋白酶(caspase)-3、caspase-9、细胞凋亡率]的影响。结果:免疫组化显示,观察组RON阳性表达率(71.88%,23/32)较对照组(27.37%,26/95)高;观察组CXCR4阳性表达率(65.63%,21/32)较对照组(12.63%,12/95)高;蛋白免疫印迹检测显示,观察组RON、CXCR4蛋白较对照组高(P<0.05);RON、CXCR4蛋白与耐药均呈正相关(P<0.05);加入RON、CXCR4抑制剂后,RON、CXCR4表达被成功抑制,且caspase-3、caspase-9、细胞凋亡率均高于阿比特龙耐药细胞株(P<0.05);Transwell实验检测细胞迁移及侵袭显示,抑制RON、CXCR4表达,细胞迁移及侵袭细胞数目均显著降低(P<0.05);RON蛋白预测阿比特龙耐药的AUC为0.789,截断值>4.11,敏感度为84.37%,特异度为61.05%(P<0.05);CXCR4蛋白预测阿比特龙耐药的AUC为0.825,截断值>3.42,敏感度为75.00%,特异度为80.00%(P<0.05);RON+CXCR4蛋白预测阿比特龙耐药的AUC为0.884(95%CI:0.815~0.934),敏感度为87.50%,特异度为83.16%(P<0.05)。结论:CRPC患者RON、CXCR4蛋白表达显著增加,与患者阿比特龙耐药密切相关,有望成为预测耐药的标志物,抑制RON、CXCR4蛋白表达,可促进CRPC阿比特龙耐药细胞的凋亡。
AIM:To study the correlation between the expression of recepteur d'origine nantais(RON)protein and CXC chemokine motif receptor 4(CXCR4)protein and abiraterone resistance in patients with castration-resistant prostate cancer(CRPC).METHODS:From January 2017 to February 2020,127 patients with CRPC who were treated with abiraterone in our hospital were selected.According to the status of drug resistance,they were divided into observation group(n=32,patients with abiraterone resistance)and control group(n=95,patients in remission).Immunohistochemistry and Western blot analysis were used to compare the expression of RON and CXCR4 protein between the two groups.Logistic regression analysis was used to conduct single-factor and multi-factor analysis of RON,CXCR4 protein and drug resistance,and receiver operating characteristic curve(ROC)and area under ROC(AUC)were used to analyze the value of RON and CXCR4 protein in predicting drug resistance.In addition,RON and CXCR4 inhibitors were added to abiraterone-resistant cell lines.The effects of the two on the apoptosis indicators of abiraterone resistance[caspase-3,caspase-9,apoptosis rate]were observed.RESULTS:Immunohistochemistry showed that the positive expression rate of RON in the observation group(71.88%,23/32)was higher than that of the control group(27.37%,26/95).The positive expression rate of CXCR4 in the observation group(65.63%,21/32)was higher than that of the control group(12.63%,12/95).Western blot detection showed that the RON and CXCR4 proteins in the observation group were higher than those in the control group(P<0.05).RON and CXCR4 protein were positively correlated with drug resistance(P<0.05).After adding RON and CXCR4 inhibitors,the expression of RON and CXCR4 was successfully inhibited,and the rates of caspase-3,caspase-9 and cell apoptosis were higher than those of abiraterone-resistant cell lines(P<0.05).The cell migration and invasion detected by Transwell experiment showed that inhibiting the expression of RON and CXCR4,the number of cell migration and invasion cells were significantly reduced(P<0.05).The AUC of RON protein predicting abiraterone resistance was 0.789,the cut-off value was>4.11,the sensitivity was 84.37%,and the specificity was 61.05%(P<0.05).The AUC of abiraterone resistance predicted by CXCR4 protein was 0.825,the cutoff value was>3.42,the sensitivity was 75.00%,and the specificity was 80.00%(P<0.05).The AUC of RON+CXCR4 protein predicting abiraterone resistance was 0.884(95%CI:0.815-0.934),the sensitivity was 87.50%,and the specificity was 83.16%(P<0.05).CONCLUSION:The expression of RON and CXCR4 protein in CRPC patients increases significantly,which is closely related to the resistance of Abiraterone in patients and is expected to become a marker for predicting drug resistance.Inhibiting the expression of RON and CXCR4 proteins can promote the apoptosis of CRPC abiraterone resistant cells.
作者
魏松长
杨红琪
张宏娟
施晓丽
任凯文
WEI Songchang;YANG Hongqi;ZHANG Hongjuan;SHI Xiaoli;REN Kaiwen(Ningbo Sixth Hospital,Ningbo 315040,Zhejiang,China;Huzhou Central Hospital,Huzhou 313000,Zhejiang,China)
出处
《中国临床药理学与治疗学》
CAS
CSCD
2021年第4期414-422,共9页
Chinese Journal of Clinical Pharmacology and Therapeutics
基金
浙江省医药卫生科技计划项目(WE7575869)。
