DNA-PKcs在铂类耐药形成过程中的动态表达及临床因素的相关性分析

Dynamics of DNA-dependent protein kinase expression in the development of platinum resistance and correlation with clinical factors

目的动态检测裸鼠铂类耐药模型DNA依赖蛋白激酶催化亚单位(DNA-PKcs)在铂类耐药形成过程的变化,分析卵巢癌患者DNA-PKcs的表达水平与临床因素的相关性,为肿瘤患者的个体化治疗提供实验依据。方法以实时荧光定量PCR技术检测DNA-PKcs mRNA的表达;Pearson相关分析卵巢癌患者DNA-PKcs的表达量与卵巢癌患者临床因素的相关性,Kaplan-Meier法分析临床因素及DNA-PKcs的表达对患者无疾病进展生存时间和总生存时间的影响;Cox回归模型分析卵巢癌预后相关因素对患者生存的影响。结果裸鼠体内铂类耐药移植瘤DNA-PKcs的表达显著低于铂类敏感对照(P=0.003),铂类敏感细胞在获得性耐药形成过程中DNA-PKcs的表达逐渐下降,耐药细胞产生以后,DNAPKcs基因的表达始终在较低的水平。Pearson分析表明DNA-PKcs的表达与患者对铂类药物初始治疗的反应和铂类耐药的产生呈显著负相关(P=0.000)。Kaplan-Meier法分析显示,FIGO分期越早、无术后残余病灶、对铂类初次治疗有效、铂类治疗敏感、DNA-PKcs高表达的患者的生存时间显著延长(P<0.05)。Cox回归模型分析发现纳入影响卵巢癌患者总生存时间的危险因素为铂类初始治疗反应(P=0.047)和铂类耐药产生(P=0.047),铂类药物治疗完全有效和部分有效患者的DNA-PKcs表达量显著高于肿瘤无消退和肿瘤增长的两组患者(P=0.000),铂类敏感患者DNA-PKcs平均表达量显著高于铂类耐药患者(P=0.000)。结论 DNA-PKcs的表达下降与铂类耐药形成相关,可能作为判断卵巢癌铂类耐药产生的潜在标志分子。

Objective To analyze the dynamics of DNA-dependent protein kinase（DNA-PKcs）expression in a nude mouse model of platinum resistance,as well as correlate the dynamics with clinicopathological characteristics of ovarian cancer patients,in order to develop an experimental system for individualized chemotherapy. Methods DNA-PKcs expression was measured by real-time fluores-cence quantitative reverse transcription-polymerase chain reaction （qRT-PCR）.Pearson correlation was used to examine associations between expression levels and clinical factors in patients with ovarian cancer.Kaplan-Meier analysis was used to examine association of DNA-PKcs expression with progression-free survival（PFS）and overall survival（OS）.Factors affecting patient survival were iden-tified by Cox regression. Result DNA-PKcs expression was significantly lower in transplanted platinum-resistant tumors than in platinum-sensitive controls （P=0.003）.Development of drug resistance was associated with a gradual decrease in DNA-PKcs expression, which remained low during the production of platinum-resistant tumor cells.Pearson analysis showed that DNA-PKcs expression correlated negatively with both patient response to platinum treatment and the level of platinum resistance （P=0.000）.Kaplan-Meier analysis showed significantly higher survival rates for patients at an early FIGO stage,patients without residual disease,patients who responded to primary platinum treatment,patients sensitive to platinum,and patients with high DNA-PKcs expression（P〈0.05）.Cox regression identified two factors affecting survival time in patients with ovarian cancer：response to primary platinum treatment （P=0.047）and platinum resistance（P=0.047）.DNA-PKcs expression was significantly higher in patients who responded completely to platinum treatment than in patients with stable or progressive tumors（P=0.000）.Similarly,DNA-PKcs expression was significantly higher in platinum-sensitive patients than in platinum-resistant ones（P=0.000）. Conclusion The development of platinum resistance may be associated with a reduction in DNA-PKcs expression,suggesting that DNA-PKcs may be a useful biomarker of platinum resistance in ovarian cancer.