铂类耐药相关基因在卵巢癌顺铂耐药形成过程中表达量的动态变化  

Dynamic expression of resistance genes during Cisplatin resistance process of ovarian cancer

作　　者：石丽君[1] 于红静[1] 李力[2] 王琪[1] 

机构地区：[1]广西医科大学附属肿瘤医院实验研究部,南宁530021 [2]广西医科大学附属肿瘤医院妇瘤科,南宁530021

出　　处：《中国癌症防治杂志》2013年第3期210-215,共6页CHINESE JOURNAL OF ONCOLOGY PREVENTION AND TREATMENT

基　　金：广西科学研究与技术开发计划项目(桂科攻1140003A-34);广西医学科学实验中心开放基金资助项目(KFJJ2010-3)

摘　　要：目的了解卵巢癌患者在铂类治疗过程中产生获得性耐药相关基因表达动态变化的情况,为临床预后的预测及个体化治疗奠定理论基础。方法采用Benjamini-Hochberg(BH)法对源于TCGA数据库(The Cancer Genome Atlas)的256例敏感和耐药患者的卵巢癌全基因表达谱数据进行差异表达基因筛选。采用DAVID软件中的KEGG模块对筛选出的差异基因进行通路富集,筛选出P<0.05的通路,对筛选出的通路所包含的基因采用成组t检验找出差异显著的基因(P<0.05)。对筛选出的基因采用COREMINE工具进行文本挖掘,找出与多药耐药及肿瘤耐药存在线性相关的基因,将其与患者预后进行分析,确定存在差异显著的基因。采用实时荧光定量PCR法检测所筛选出的基因在裸鼠诱导耐药模型不同给药阶段的表达变化情况。结果 BH法共筛选出306个差异表达基因,其中上调基因110个,下调基因196个。DAVID软件的KEGG模块分别筛选出5条上调及4条下调通路,成组t检验筛选出有差异的基因共37个,其中上调基因18个,下调基因19个。COREMINE工具检索出与多药耐药及肿瘤耐药存在线性相关的上调基因为ITPA、IMPDH2、RPS7、PDE5A和PDE4D,下调基因为GNAS、CFTR、BUB3、PRKDC、RBL2、SMC1A、CALR、CCNE2及CHEK1。生存分析结果提示CALR及PRKDC基因的表达与患者生存时间有关,CALR和PRKDC基因高表达组的患者生存时间长于低表达组。qRT-PCR检测发现,CALR和PRKDC基因随顺铂注射次数增多,在SKOV3-GFP及SKOV3/DDPⅱ肿瘤组织中的表达量逐渐降低。结论 CALR与PRKDC基因可能与卵巢癌铂类耐药及患者的预后密切相关,且随着耐药的产生,CALR和PRKDC基因的表达量逐渐降低。Objective To study the dynamic expression of resistance genes during chemotherapy resistance process, so as to provide evidences for exploring reversal targets and reversal treatment. Methods Adopt Benjamini-Hochberg（BH）to analyse expression profile data of ovarian cancer who provided by TCGA,then use KEGG of DAVID to enrich the pathway,then employ T test to measure them again,use COREMINE to select some genes which is associated with multiple drug resistant and drug resistance of neoplasm.Take the differentially expressed gene to conduct survival analysis,find out the genes which is significant. Then employ qRT-PCR to examine the expression of them in SKOV3-GFP and SKOV3/DDP ii tumor. Result 306 differentially expressed genes were found in Microarray, of which 110 had increased expression and 196 had low expression. KEGG of DAVID enrichment 5 up-regulate-pathway and 4 down- regulate-pathway.T test sift out 18 up-regulate genes and 19 clown-regulate genes.COREMINE search out 5 up-regulate genes,for example ： ITPA ,IMPDH2 ,RPS7 ,PDE5A and PDE4D, down-regurate genes as GNAS,CFTR,BUB3 ,PRKDC ,RBL2,SMC 1A ,CALR, CCNE2 and CHEK1. Survival analysis shows that overall survival was longer when comparing high expression team of CALR and PRKDC with low expression team.Expression of CALR and PRKDC gradually reduces as Cisplatin injection times increase in SKOV3- GFP and SKOV3/DDP ii tumor. Conclusion Expression of CALR and PRKDC may be associated with cisplatin resistance.So reduc- ing expression of CALR and PRKDC mean that these ovarian cancer patientsmay have resistance to cisplatin.

关 键 词：卵巢肿瘤 卵巢上皮性癌 耐药相关基因 顺铂 基因表达 动态变化 

分 类 号：R737.31[医药卫生—肿瘤]