利用毒理与耐药基因芯片对胶质瘤化疗后复发相关新候选基因的探索性研究
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摘要
目的:研究化疗前后不同时期胶质瘤组织中毒理与耐药基因表达的变化趋势以及应激反应的分子改变,初步探讨胶质瘤化疗后复发相关的新候选基因。
方法:利用人胶质瘤细胞系U251细胞构建裸鼠皮下异位胶质瘤移植模型。通过顺铂对荷瘤裸鼠进行化疗(5mg/kg/d连续腹腔注射4-5天),建立胶质瘤化疗和化疗后复发模型。在结束给药的次日取瘤作为化疗结束组胶质瘤;化疗结束后1周左右、胶质瘤较化疗前明显减小但还没开始长大时,取瘤作为胶质瘤最小组胶质瘤;在化疗结束后10-14天、胶质瘤迅速长大时,取瘤作为复发组胶质瘤。利用功能分类基因芯片检测化疗前后不同时期胶质瘤组织中毒理与耐药基因的表达变化及应激反应的分子改变。应用SPSS15.0统计软件对基因芯片数据进行统计分析。
结果:ABCC1基因在化疗结束组、胶质瘤最小组和复发组胶质瘤组织中的表达依次增强。ABCC5和BCL2基因在化疗结束组表达增强,在胶质瘤最小组表达显著减弱,在胶质瘤复发组表达显著增强。HSPB2基因在化疗结束组表达增强,胶质瘤最小组表达最强,在复发组其表达减弱;NFKB1、NFKBIA和BAG1基因在化疗结束组表达减弱,在胶质瘤最小组和复发组逐渐增强。化疗后HSPA6和PPARGC1A基因表达逐渐减弱,在胶质瘤最小组其表达最弱,胶质瘤复发时其表达再增强。
PPARGC1A与NFKB1、BAX与PPARGC1A均呈正相关;PPARGC1A与BCL2、HSPB2与PPARGC1A、HSPB2与BAX均呈负相关。
结论:1.化疗前后不同时间胶质瘤组织中部分毒理与耐药基因的表达动态变化且存在时间窗口特征,其中ABCC1、ABCC5、HSPB2、NFKB1、PPARGC1A、ATM、BAG1和BCL2为在胶质瘤化疗后复发机制中可能起重要作用的候选基因。
2.化疗后胶质瘤细胞凋亡基因的启动可能与PPARGC1A、NFKB等应激反应相关基因有关,这些基因表达水平的改变可能与其应激通路有关。
Objective: To study the expression of toxicology & drug resistance gene and molecular related to stress response in pre-and post-chemotherapeutic glioma, and to explore novel candidate genes related to postchemotherapeutic glioma relapse.
Methods: Ectopicly subcutaneous glioma transplantation models in nude mice were established by injection of human glioma cell line U251 cells. Tumor-beared nude mice were treated by the intraperitoneal injection of cisplatin (at the dose of 5mg/kg/d for 4-5 days continuously), chemotherapeutic and recurrent glioma model after chemotherapy were established. Gliomas were harvested as a group of gliomas after chemotherapy on the next day of completion of chemotherapy; about 1 week after chemotherapy gliomas were harvested as a group of smallest glioma after chemotherapy when gliomas significantly reduced but did not grow again ;about 10 to14 days after chemotherapy gliomas were harvested as a group of recurrence gliomas after chemotherapy when gliomas recurred rapidly. Expression of toxicology & drug resistance gene and molecular related to stress response in pre-and post-chemotherapeutic glioma were detected using oligo toxicology & drug resistance microarrays. Data in gene chip was analyzed by statistical software SPSS15.0.
Results:Expression of ABCC1 increased gradually in gliomas after chemotherapy. Expression of ABCC5 and BCL2 increased in gliomas at completion of chemotherapy and significantly decreased when gliomas was smallest, and increased obviously when gliomas recurred. Expression of HSPB2 increased in gliomas after chemotherapy, its expression was highest when gliomas was smallest and decreased when gliomas recurred. Expression of NFKB1、NFKBIA and BAG1 decreased in gliomas at completion of chemotherapy and increased gradually subsequently. Expression of HSPA6 and PPARGC1A decreased in gliomas gradually after chemotherapy and increased again when gliomas recurred.
NFKB1 and BAX were both positively correlated with PPARGC1A; BCL2 and HSPB2 were both negatively correlated with PPARGC1A and HSPB2 was negatively correlated with BAX too.
Conclusion: 1. Expression of some genes related to toxicity and drug resistance in gliomas changed ambulatorily pre- and post-chemotherapy and there was a time window. ABCC1、ABCC5、HSPB2、NFKB1、PPARGC1A、ATM、BAG1 and BCL2 in gliomas are candidate genes which might play an important role in glioma recurrence after chemotherapy. 2. Activation of apoptosis gene of glioma cells after chemotherapy might correlate with PPARGC1A、NFKB and other stress-related genes,and expression change of these genes might relate to stress pathway.
方法:利用人胶质瘤细胞系U251细胞构建裸鼠皮下异位胶质瘤移植模型。通过顺铂对荷瘤裸鼠进行化疗(5mg/kg/d连续腹腔注射4-5天),建立胶质瘤化疗和化疗后复发模型。在结束给药的次日取瘤作为化疗结束组胶质瘤;化疗结束后1周左右、胶质瘤较化疗前明显减小但还没开始长大时,取瘤作为胶质瘤最小组胶质瘤;在化疗结束后10-14天、胶质瘤迅速长大时,取瘤作为复发组胶质瘤。利用功能分类基因芯片检测化疗前后不同时期胶质瘤组织中毒理与耐药基因的表达变化及应激反应的分子改变。应用SPSS15.0统计软件对基因芯片数据进行统计分析。
结果:ABCC1基因在化疗结束组、胶质瘤最小组和复发组胶质瘤组织中的表达依次增强。ABCC5和BCL2基因在化疗结束组表达增强,在胶质瘤最小组表达显著减弱,在胶质瘤复发组表达显著增强。HSPB2基因在化疗结束组表达增强,胶质瘤最小组表达最强,在复发组其表达减弱;NFKB1、NFKBIA和BAG1基因在化疗结束组表达减弱,在胶质瘤最小组和复发组逐渐增强。化疗后HSPA6和PPARGC1A基因表达逐渐减弱,在胶质瘤最小组其表达最弱,胶质瘤复发时其表达再增强。
PPARGC1A与NFKB1、BAX与PPARGC1A均呈正相关;PPARGC1A与BCL2、HSPB2与PPARGC1A、HSPB2与BAX均呈负相关。
结论:1.化疗前后不同时间胶质瘤组织中部分毒理与耐药基因的表达动态变化且存在时间窗口特征,其中ABCC1、ABCC5、HSPB2、NFKB1、PPARGC1A、ATM、BAG1和BCL2为在胶质瘤化疗后复发机制中可能起重要作用的候选基因。
2.化疗后胶质瘤细胞凋亡基因的启动可能与PPARGC1A、NFKB等应激反应相关基因有关,这些基因表达水平的改变可能与其应激通路有关。
Objective: To study the expression of toxicology & drug resistance gene and molecular related to stress response in pre-and post-chemotherapeutic glioma, and to explore novel candidate genes related to postchemotherapeutic glioma relapse.
Methods: Ectopicly subcutaneous glioma transplantation models in nude mice were established by injection of human glioma cell line U251 cells. Tumor-beared nude mice were treated by the intraperitoneal injection of cisplatin (at the dose of 5mg/kg/d for 4-5 days continuously), chemotherapeutic and recurrent glioma model after chemotherapy were established. Gliomas were harvested as a group of gliomas after chemotherapy on the next day of completion of chemotherapy; about 1 week after chemotherapy gliomas were harvested as a group of smallest glioma after chemotherapy when gliomas significantly reduced but did not grow again ;about 10 to14 days after chemotherapy gliomas were harvested as a group of recurrence gliomas after chemotherapy when gliomas recurred rapidly. Expression of toxicology & drug resistance gene and molecular related to stress response in pre-and post-chemotherapeutic glioma were detected using oligo toxicology & drug resistance microarrays. Data in gene chip was analyzed by statistical software SPSS15.0.
Results:Expression of ABCC1 increased gradually in gliomas after chemotherapy. Expression of ABCC5 and BCL2 increased in gliomas at completion of chemotherapy and significantly decreased when gliomas was smallest, and increased obviously when gliomas recurred. Expression of HSPB2 increased in gliomas after chemotherapy, its expression was highest when gliomas was smallest and decreased when gliomas recurred. Expression of NFKB1、NFKBIA and BAG1 decreased in gliomas at completion of chemotherapy and increased gradually subsequently. Expression of HSPA6 and PPARGC1A decreased in gliomas gradually after chemotherapy and increased again when gliomas recurred.
NFKB1 and BAX were both positively correlated with PPARGC1A; BCL2 and HSPB2 were both negatively correlated with PPARGC1A and HSPB2 was negatively correlated with BAX too.
Conclusion: 1. Expression of some genes related to toxicity and drug resistance in gliomas changed ambulatorily pre- and post-chemotherapy and there was a time window. ABCC1、ABCC5、HSPB2、NFKB1、PPARGC1A、ATM、BAG1 and BCL2 in gliomas are candidate genes which might play an important role in glioma recurrence after chemotherapy. 2. Activation of apoptosis gene of glioma cells after chemotherapy might correlate with PPARGC1A、NFKB and other stress-related genes,and expression change of these genes might relate to stress pathway.
引文
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