人胰腺癌细胞中对5-氟尿嘧啶耐药相关基因的检测分析
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摘要
背景和目的:化疗耐药的发生限制了5-氟尿嘧啶(5-FU)对胰腺癌的治疗疗效,明确化疗耐药机制,进行针对性的治疗是解决化疗耐药的有效方法。目前的研究提示很多耐药机制都涉及到基因水平的变化。随着基因芯片技术的发展,我们可以通过对在体外筛选获得的不同胰腺癌5-FU耐药细胞表型及其原代细胞进行基因表达数据对比分析,找出不同耐药表型细胞相对原代细胞的基因表达改变情况,从而发现一些可能的与胰腺癌细胞5-FU耐药相关的重要基因或通路。
方法:用不断增加浓度的5-FU反复进行胰腺癌MIAPaCa-2细胞培养直到细胞完全耐受不同浓度的5-FU,并且能在所耐受相应浓度的5-FU中维持稳定生长至少三个月,最终获得二株稳定的耐不同浓度5-FU的MIAPaCa-2细胞表型。再用含人类20,000个检测探针的基因芯片对原代MIAPaCa-2细胞和二个不同耐药表型的基因进行检测分析。基因芯片结果由Codelink系统软件进行数据分析。结合基因功能分析筛选出的基因再进行实时PCR检测验证。
结果:我们成功地获得了二种耐药细胞表型:低耐药浓度表型MIA-FU-2.4和高耐药浓度表型MIA-FU-10.0,这二种表型分别能在浓度为2.4μg/ml和10.0μg/ml的5-FU中稳定生长。对不同浓度5-FU耐药的胰腺癌细胞表型和胰腺癌原代细胞进行基因数据对比分析,结果提示耐药可能与广泛的基因表达改变相关。在低耐药表型MIA-FU-2.4和高耐药表型MIA-FU-10.0中分别有1075种和1628种基因的表达情况存在差异。通过与基因数据库的对比分析,发现这些差异表达基因主要涉及细胞周期,细胞粘附,信号转导,DNA修复和凋亡等多种细胞生物学功能。
讨论:研究结果提示胰腺癌MIAPaCa-2细胞株5-FU耐药的发生主要与调控多种细胞生物学功能的基因表达水平改变相关,如:凋亡、DNA修复和细胞周期等。同时还涉及这些差异表达基因共同参与的一些信号转导途径的改变,所以在化疗耐药的研究中可以更多地关注参与细胞生物学功能调控的相关基因及途径,指导临床治疗,改善化疗疗效。
Background & Aims: Using gene expression data, we compared the expression profile of 5-fluorouracil (5-FU) resistance in pancreatic cancer cells after in vitro selection low- and high-resistance phenotypes. The aims of our study were to identify genes showing altered expression in resistant derivatives, as well as several central genes or important pathways that were associated with 5-FU resistance in pancreatic cancer cells.
Methods: The 5-FU-resistant MIAPaCa-2 derivatives were developed through exposure to increasing concentrations of 5-FU with repeated subcultures until the cells became fully resistant to 5-FU. Gene array analysis of the 5-FU-resistant MIAPaCa-2 derivatives and the parent cell line was performed using a Uniset Human 20K I Codelink Bioarray. Data were analyzed with CodeLink System Software. The expression profiling of selected genes were confirmed by real-time PCR assays. Results: We got successively two resistant derivatives, the low-resistance phenotype MIA-FU-2.4 and the high-resistance phenotype MIA-FU-10.0, These two derivatives can grow stably in 2.4μg/ml and 10.0μg/ml of 5-FU concentration respectively. Analysis of array data showed that the resistance of 5-FU in pancreatic cancer cell involved in widespread transcriptional activation. In MIA-FU-2.4 and MIA-FU-10.0, we identified respectively 1075 and 1628 differentially expressed genes. The biological functions of these genes included cell cycle, cell adhesion, signal transduction, DNA repair and apoptosis et al.
Conclusions: Our data suggest that 5-FU resistance development in pancreatic cancer cell MIAPaCa-2 involves in many aspects of the biological functions and might be mainly attributed to apoptosis, DNA repair and cell cycle mechanisms and some signal transductions or some pivotal genes.
方法:用不断增加浓度的5-FU反复进行胰腺癌MIAPaCa-2细胞培养直到细胞完全耐受不同浓度的5-FU,并且能在所耐受相应浓度的5-FU中维持稳定生长至少三个月,最终获得二株稳定的耐不同浓度5-FU的MIAPaCa-2细胞表型。再用含人类20,000个检测探针的基因芯片对原代MIAPaCa-2细胞和二个不同耐药表型的基因进行检测分析。基因芯片结果由Codelink系统软件进行数据分析。结合基因功能分析筛选出的基因再进行实时PCR检测验证。
结果:我们成功地获得了二种耐药细胞表型:低耐药浓度表型MIA-FU-2.4和高耐药浓度表型MIA-FU-10.0,这二种表型分别能在浓度为2.4μg/ml和10.0μg/ml的5-FU中稳定生长。对不同浓度5-FU耐药的胰腺癌细胞表型和胰腺癌原代细胞进行基因数据对比分析,结果提示耐药可能与广泛的基因表达改变相关。在低耐药表型MIA-FU-2.4和高耐药表型MIA-FU-10.0中分别有1075种和1628种基因的表达情况存在差异。通过与基因数据库的对比分析,发现这些差异表达基因主要涉及细胞周期,细胞粘附,信号转导,DNA修复和凋亡等多种细胞生物学功能。
讨论:研究结果提示胰腺癌MIAPaCa-2细胞株5-FU耐药的发生主要与调控多种细胞生物学功能的基因表达水平改变相关,如:凋亡、DNA修复和细胞周期等。同时还涉及这些差异表达基因共同参与的一些信号转导途径的改变,所以在化疗耐药的研究中可以更多地关注参与细胞生物学功能调控的相关基因及途径,指导临床治疗,改善化疗疗效。
Background & Aims: Using gene expression data, we compared the expression profile of 5-fluorouracil (5-FU) resistance in pancreatic cancer cells after in vitro selection low- and high-resistance phenotypes. The aims of our study were to identify genes showing altered expression in resistant derivatives, as well as several central genes or important pathways that were associated with 5-FU resistance in pancreatic cancer cells.
Methods: The 5-FU-resistant MIAPaCa-2 derivatives were developed through exposure to increasing concentrations of 5-FU with repeated subcultures until the cells became fully resistant to 5-FU. Gene array analysis of the 5-FU-resistant MIAPaCa-2 derivatives and the parent cell line was performed using a Uniset Human 20K I Codelink Bioarray. Data were analyzed with CodeLink System Software. The expression profiling of selected genes were confirmed by real-time PCR assays. Results: We got successively two resistant derivatives, the low-resistance phenotype MIA-FU-2.4 and the high-resistance phenotype MIA-FU-10.0, These two derivatives can grow stably in 2.4μg/ml and 10.0μg/ml of 5-FU concentration respectively. Analysis of array data showed that the resistance of 5-FU in pancreatic cancer cell involved in widespread transcriptional activation. In MIA-FU-2.4 and MIA-FU-10.0, we identified respectively 1075 and 1628 differentially expressed genes. The biological functions of these genes included cell cycle, cell adhesion, signal transduction, DNA repair and apoptosis et al.
Conclusions: Our data suggest that 5-FU resistance development in pancreatic cancer cell MIAPaCa-2 involves in many aspects of the biological functions and might be mainly attributed to apoptosis, DNA repair and cell cycle mechanisms and some signal transductions or some pivotal genes.
引文
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