胶质瘤耐药基因的筛选及胶质母细胞瘤细胞系TLC1的建立和鉴定
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摘要
[目的]胶质瘤是最常见的脑肿瘤，其中弥散性浸润的星形细胞瘤约占60％。手术和放射疗法是治疗恶性胶质瘤的主要手段。胶质瘤的治疗和预后受多种因素影响，化疗效果不理想有多方面的原因：首先，对中枢神经系统肿瘤有效化疗药物的抗瘤谱不能完全肯定，因此很难根据肿瘤细胞的病理类型来选择药物；其次，胶质瘤本身对化疗药物耐药，未能针对不同个体与肿瘤类型选择敏感药物也是重要的原因；还有，选用难以通过血脑屏障、与肿瘤细胞动力学特性不符的化疗药物也会影响化疗效果。因而进行胶质瘤化学治疗敏感性、抗药性的检测和研究，对指导临床化疗药物的选择具有重要意义。本研究通过从临床收集胶质瘤标本MTT区分化疗药物敏感和耐药组织、诱导胶质瘤细胞系建立耐药细胞株、原代培养建立新的胶质母细胞瘤细胞系，利用基因芯片分别比较基因表达谱的差异，筛选出与化疗药物耐受相关的基因并证实其表达。为对不同个体胶质瘤化疗药物的选择提供有力的理论依据和应用工具，同时也为其他肿瘤特异性化疗药物的选择奠定基础。
[方法]
1．原发性耐药相关基因的筛选方法：收集临床手术切除的胶质瘤组织，原代培养的肿瘤细胞由MTT体外测定VM-26对胶质瘤的抑制率，按照45ng(1PPC)时，抑制率＞30％为敏感，＜30％为耐药作为标准，筛选出对化疗药物VM-26耐药和敏感的病例，cDNA芯片分析基因表达的变化，验证分析结果，筛选出与耐药相关的基因并验证：
2．继发性耐药相关基因的筛选方法：选用人胶质瘤细胞系SHG44为靶细胞，每4000个细胞用药量从低浓度0．135ng起始，逐步递增至VM-26用量达4．5ng／4000细胞，诱导建立对VM-26耐药的细胞株。应用人类cDNA表达谱芯片检测耐药和敏感细胞基因表达谱的变化，筛选出与耐药有关的基因并验证；
3．原代培养的胶质母细胞瘤细胞历时14个月，连续传代80余代后，建立了一个新的胶质母细胞瘤细胞系并进行鉴定。
[结果]
1．3例VM-26敏感病例和3例耐药病例，分别组成两组进行cDNA芯片分析，结果经聚类分析后共筛选出有表达差异的基因21个，其中表达上调的基因6个，表达下调的基因15个；基因HDAC1经半定量PCR证实在6例组织中都有表达，趋势与芯片结果一致。
2．历时5个月建立了稳定耐药的细胞株SHG44／VM-26，亲代细胞对VM-26的IC_(50)为0．99μg／ml，耐药细胞对VM-26的IC_(50)为52．06μg／ml，是亲代细胞的52．58倍，二者之间具有显著性差异(P＜0．01)；亲代细胞倍增时间为25．6小时，耐药细胞倍增时间为48．9小时，明显长于亲代细胞；cDNA芯片共筛选出有表达差异的基因121个，其中表达上调的基因37个，表达下调的基因84个；半定量PCR证实基因MDR1、NGFR、HSP22在耐药细胞中的表达量高于在亲代细胞中的表达量；基因CX IX、CDKN3和NADE在耐药细胞中的表达量低于在亲代细胞中的表达量，与基因芯片结果趋势一致。
3．一例胶质母细胞瘤手术切除后经原代培养、连续传代后建立了一个新的胶质母细胞瘤细胞系TLC1，稳定传代80余代，倍增时间38．5小时，克隆形成率为5．13％，流式细胞仪分析DI为0．86，细胞系是亚二倍体，具有浸润生长特性，凝集试验证实其为恶性肿瘤细胞。第10、23、38、44、52代TLC1细胞对VM-26的IC_(50)分别为910．8、1218．2、75、72．8、和131．2ng／ml，第10、23代与第38、44、52代有显著性差异(P＜0．05)。
[结论]
1．MDR1在耐药细胞中的高表达证实了耐药细胞的诱导成功，cDNA芯片杂交分析系统的稳定可靠。
2．胶质瘤原发性耐药可能与CIDEB、ENPEP、HDAC1、JUND、STK17B、TSPAN7、PRKRIR、BRD2、AKAP10、ABI1、ZMYND11、ALDH2有关，验证后与HDAC1高表达相关，其耐药机理需要进一步研究。
3．继发性耐药与基因MDR1、NGFR、HSP22的高表达相关，与基因CX IX、CDKN3和NADE的低表达相关，尚需对以上基因的耐药机理进一步研究。
4．原代培养成功建立了一个新的胶质母细胞瘤细胞系，经鉴定具有肿瘤细胞的特征，其耐药程度随着传代数量的增加而降低。
Objective Malignant gliomas are the most common primary brain tumors inadults.In clinical,chemotherapy is one of the major methods for treatingmalignant glioma.However,the clinical effectiveness of chemotherapy is oftenlimited by the emergence of drug-resistant tumor cells.One of the most criticalissues to be solved in regard to cancer chemotherapy is the need to establish amethod for predicting efficacy or toxicity of anticancer drugs for individual patients.To this end,two experimental approaches were used in this study:1.To determinethose genes whose expression were changed in cells with acquired resistance toVM-26,2.To analyze the genes which were differentially expressing between theclinical drug sensitive and drug resistance individuals.This double strategy was todiscover genes that were differentially expressing once the resistance had beenestablished and had already suffered changes in their expression naturally.
Method
1.Six fresh glioma specimens obtained immediately after surgical resectionwere primary cultured.After divided into two groups according their inhibitionrates by Cytotoxicity Assays,cDNA microarray was used to identify differentexpressing genes among those tissues.
2.Glioma cell line SHG44 was successive exposure to increasing amounts ofVM-26 for up to 4 months and then cells were cultured in DMEM,in which theconcentration of VM-26 was 4.5ng/4000 cells for 1 month.Cell proliferation andcytotoxicity were serially monitored and cDNA microarray was used to identifydifferent expressing genes between the parent cell and VM-26 resistant cellSHG44/VM-26.
3.Established a new glioma cell line by primary culture and identified it.
Result
1.There were 3 glioma cases in the drug resistance group and 3 glioma casesin the drug sensitive group.After the cDNA microarray analysis,data wasclustered by SAM software,21 genes were screened out as different expressinggenes,6 of them were up regulated and 15 of them were down regulated.Althoughthe high expression of gene HDAC1 was authenticated by semi-quantitative PCR,there was no statistic difference between the two groups.
2.The IC_(50) of drug resistance cell SHG44/VM-26 is 52.06μg/ml,which is52.58 times higher than that of parent cell SHG44,whose IC_(50) is 0.99μg/ml.Thedoubling time of SHG44/VM-26 is 48.9 hours,longer than that of SHG44,whosedoubling time is 25.6 hours.The number of different expressing genes screened bycDNA microarray was 121,37 of them were up regulated and 84 of them were downregulated.The high expressions of gene MDR1,NGFR,HSP22 and the lowexpressions of gene CX IX,CDKN3,NADE were authenticated bysemi-quantitative PCR.The expressions of MDR1,NGFR,HSP22 inSHG44/VM-26 were 3.92,1.81,2.06 times higher than that in SHG44 respectively,and the expressions of CX IX,CDKN3,NADE in SHG44/VM-26 were 0.13,0.18,0.81 times of that in SHG44.
3.A new glioma cell line was established and had been passaged more than80 generations at present.Doubling time of it is 38.5 hours and the rate of colonyforming is 5.13%.The result of FCM demonstrated this glioma cell line washypodiploid.It had the infiltration activity.Conclusion The high expression of MDR1 certificate that both the establishmentof drug resistant cell line SHG44/VM-26 and the cDNA microarray analysis systemare stable.High expressions of NGFR,HSP22 and low expressions of CX IX, CDKN3,NADE are related to the drug resistance.Whether the high expression ofHDAC1 is correlate to drug resistance can not be confirmed in this study.
[方法]
1．原发性耐药相关基因的筛选方法：收集临床手术切除的胶质瘤组织，原代培养的肿瘤细胞由MTT体外测定VM-26对胶质瘤的抑制率，按照45ng(1PPC)时，抑制率＞30％为敏感，＜30％为耐药作为标准，筛选出对化疗药物VM-26耐药和敏感的病例，cDNA芯片分析基因表达的变化，验证分析结果，筛选出与耐药相关的基因并验证：
2．继发性耐药相关基因的筛选方法：选用人胶质瘤细胞系SHG44为靶细胞，每4000个细胞用药量从低浓度0．135ng起始，逐步递增至VM-26用量达4．5ng／4000细胞，诱导建立对VM-26耐药的细胞株。应用人类cDNA表达谱芯片检测耐药和敏感细胞基因表达谱的变化，筛选出与耐药有关的基因并验证；
3．原代培养的胶质母细胞瘤细胞历时14个月，连续传代80余代后，建立了一个新的胶质母细胞瘤细胞系并进行鉴定。
[结果]
1．3例VM-26敏感病例和3例耐药病例，分别组成两组进行cDNA芯片分析，结果经聚类分析后共筛选出有表达差异的基因21个，其中表达上调的基因6个，表达下调的基因15个；基因HDAC1经半定量PCR证实在6例组织中都有表达，趋势与芯片结果一致。
2．历时5个月建立了稳定耐药的细胞株SHG44／VM-26，亲代细胞对VM-26的IC_(50)为0．99μg／ml，耐药细胞对VM-26的IC_(50)为52．06μg／ml，是亲代细胞的52．58倍，二者之间具有显著性差异(P＜0．01)；亲代细胞倍增时间为25．6小时，耐药细胞倍增时间为48．9小时，明显长于亲代细胞；cDNA芯片共筛选出有表达差异的基因121个，其中表达上调的基因37个，表达下调的基因84个；半定量PCR证实基因MDR1、NGFR、HSP22在耐药细胞中的表达量高于在亲代细胞中的表达量；基因CX IX、CDKN3和NADE在耐药细胞中的表达量低于在亲代细胞中的表达量，与基因芯片结果趋势一致。
3．一例胶质母细胞瘤手术切除后经原代培养、连续传代后建立了一个新的胶质母细胞瘤细胞系TLC1，稳定传代80余代，倍增时间38．5小时，克隆形成率为5．13％，流式细胞仪分析DI为0．86，细胞系是亚二倍体，具有浸润生长特性，凝集试验证实其为恶性肿瘤细胞。第10、23、38、44、52代TLC1细胞对VM-26的IC_(50)分别为910．8、1218．2、75、72．8、和131．2ng／ml，第10、23代与第38、44、52代有显著性差异(P＜0．05)。
[结论]
1．MDR1在耐药细胞中的高表达证实了耐药细胞的诱导成功，cDNA芯片杂交分析系统的稳定可靠。
2．胶质瘤原发性耐药可能与CIDEB、ENPEP、HDAC1、JUND、STK17B、TSPAN7、PRKRIR、BRD2、AKAP10、ABI1、ZMYND11、ALDH2有关，验证后与HDAC1高表达相关，其耐药机理需要进一步研究。
3．继发性耐药与基因MDR1、NGFR、HSP22的高表达相关，与基因CX IX、CDKN3和NADE的低表达相关，尚需对以上基因的耐药机理进一步研究。
4．原代培养成功建立了一个新的胶质母细胞瘤细胞系，经鉴定具有肿瘤细胞的特征，其耐药程度随着传代数量的增加而降低。
Objective Malignant gliomas are the most common primary brain tumors inadults.In clinical,chemotherapy is one of the major methods for treatingmalignant glioma.However,the clinical effectiveness of chemotherapy is oftenlimited by the emergence of drug-resistant tumor cells.One of the most criticalissues to be solved in regard to cancer chemotherapy is the need to establish amethod for predicting efficacy or toxicity of anticancer drugs for individual patients.To this end,two experimental approaches were used in this study:1.To determinethose genes whose expression were changed in cells with acquired resistance toVM-26,2.To analyze the genes which were differentially expressing between theclinical drug sensitive and drug resistance individuals.This double strategy was todiscover genes that were differentially expressing once the resistance had beenestablished and had already suffered changes in their expression naturally.
Method
1.Six fresh glioma specimens obtained immediately after surgical resectionwere primary cultured.After divided into two groups according their inhibitionrates by Cytotoxicity Assays,cDNA microarray was used to identify differentexpressing genes among those tissues.
2.Glioma cell line SHG44 was successive exposure to increasing amounts ofVM-26 for up to 4 months and then cells were cultured in DMEM,in which theconcentration of VM-26 was 4.5ng/4000 cells for 1 month.Cell proliferation andcytotoxicity were serially monitored and cDNA microarray was used to identifydifferent expressing genes between the parent cell and VM-26 resistant cellSHG44/VM-26.
3.Established a new glioma cell line by primary culture and identified it.
Result
1.There were 3 glioma cases in the drug resistance group and 3 glioma casesin the drug sensitive group.After the cDNA microarray analysis,data wasclustered by SAM software,21 genes were screened out as different expressinggenes,6 of them were up regulated and 15 of them were down regulated.Althoughthe high expression of gene HDAC1 was authenticated by semi-quantitative PCR,there was no statistic difference between the two groups.
2.The IC_(50) of drug resistance cell SHG44/VM-26 is 52.06μg/ml,which is52.58 times higher than that of parent cell SHG44,whose IC_(50) is 0.99μg/ml.Thedoubling time of SHG44/VM-26 is 48.9 hours,longer than that of SHG44,whosedoubling time is 25.6 hours.The number of different expressing genes screened bycDNA microarray was 121,37 of them were up regulated and 84 of them were downregulated.The high expressions of gene MDR1,NGFR,HSP22 and the lowexpressions of gene CX IX,CDKN3,NADE were authenticated bysemi-quantitative PCR.The expressions of MDR1,NGFR,HSP22 inSHG44/VM-26 were 3.92,1.81,2.06 times higher than that in SHG44 respectively,and the expressions of CX IX,CDKN3,NADE in SHG44/VM-26 were 0.13,0.18,0.81 times of that in SHG44.
3.A new glioma cell line was established and had been passaged more than80 generations at present.Doubling time of it is 38.5 hours and the rate of colonyforming is 5.13%.The result of FCM demonstrated this glioma cell line washypodiploid.It had the infiltration activity.Conclusion The high expression of MDR1 certificate that both the establishmentof drug resistant cell line SHG44/VM-26 and the cDNA microarray analysis systemare stable.High expressions of NGFR,HSP22 and low expressions of CX IX, CDKN3,NADE are related to the drug resistance.Whether the high expression ofHDAC1 is correlate to drug resistance can not be confirmed in this study.
引文
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