羟基喜树碱联合靶向Smac基因对前列腺癌细胞凋亡的影响
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摘要
第一部分前列腺特异性抗原启动子/增强子的克隆及重组质粒的构建和鉴定
目的:利用前列腺特异性抗原(PSA)组织特异性表达的特点,克隆出其上游增强子(PSAE)和启动子(PSAP)片断并对其表达效率和组织特异性表达进行初步研究。
方法:从前列腺癌组织提取基因组DNA,并采用PCR方法分别扩增PSA增强子和启动子序列;利用报告基因pEGFP-1,分别构建含不同调控序列的表达载体;脂质体介导基因转染不同细胞并观察绿色荧光蛋白(GFP)的表达情况。
结果:成功构建质粒pPSAE-EGFP、pPSAP-EGFP、pPSAE-PSAP-EGFP;转染结果显示pPSAE-PSAP-EGFP在前列腺癌细胞PC-3中的荧光强度明显高于pPSAP-EGFP,pPSAE-EGFP同样观察到荧光表达,说明PSA增强子能显著提高PSA启动子的转录能力,并可能具有单独调控基因表达的能力。
结论:PSA增强子和启动子的共同调控可以提高基因表达的有效性和细胞特异性,为前列腺癌的临床基因治疗提供实验依据。羟基喜树碱;;前列腺肿瘤;;凋亡;;化疗
第三部分HCPT联合Smac基因对前列腺癌PC-3细胞的促凋亡作用
目的:利用PSA增强子、启动子构建携带Smac基因、人PSAE/PSAP调控的前列腺特异性真核表达载体,并联合低剂量HCPT,观察其对前列腺癌PC-3细胞的促凋亡作用。
方法:分子生物学方法构建重组真核表达载体;脂质体介导Smac基因转染前列腺癌PC-3细胞,并联合应用低剂量HCPT促进凋亡,台盼蓝染色观察细胞活性,MTT比色分析检测癌细胞抑制率,流式细胞术检测细胞凋亡,逆转录聚合酶链反应检测Smac、XIAP、caspase-3的表达。
结果:成功构建由人PSAE-PSAP调节的含Smac基因的重组载体pPSAE-PSAP-Smac;在转染pPSAE-PSAP-Smac的细胞中,只有PC-3细胞观察到明显抑制(P<0.05)。RT-PCR检测发现转染Smac基因后,Smac mRNA表达水平明显增加(P<0.05),PSAE-PSAP调节的Smac的表达也高于CMV启动子调控的Smac表达(P<0.05)。另外XIAP的表达水平在转染Smac及联合化疗药物后分别降低67.53%和76.95% (P<0.01);而caspase-3 mRNA的含量分别是正常对照的3.94倍和4.31倍(P<0.01)。MTT法检测发现,HCPT和Smac基因对细胞均有抑制作用;HCPT组、pPSAE-PSAP-Smac组、HCPT+ pPSAE-PSAP-Smac组的细胞抑制率分别为25.39%、30.76%、70.91%。流式细胞仪检测显示转染组在加入HCPT后,细胞的凋亡率明显增加,较HCPT组和pPSAE-PSAP-Smac组分别增加22.84 %和20.02 % (P<0.01)。
结论: Smac在癌细胞中的活化表达可以明显增强细胞在刺激信号下的凋亡,其作用机理是通过抑制凋亡抑制蛋白IAPs,解除了对凋亡下游效应半胱氨酸蛋白酶caspase的抑制活性。在与低剂量HCPT联合作用于PC-3细胞时,更能显著增加细胞凋亡率。
PART 1 Construction and Identification of Recombinant Plasmids with Prostate-Specific Antigen Enhancer and Promoter in Gene Expression Regulation
OBJECTIVE: To study the expression efficiency and specificity of prostate specific antigen (PSA) enhancer/promoter in a possible targeted gene therapy scheme for prostate cancer.
METHODS: Genomic DNA was obtained from prostate cancer tissues. PSA enhancer and promoter sequences were amplified using PCR method, then the two fragments were cloned into plasmid pEGFP-1 to construct the expression vectors. After transfecting into different cell lines, the expression status was observed in fluorecent microscopic examination method.
RESULTS: The recombinant plasmids (pPSAE-EGFP, pPSAP-EGFP and pPSAE-PSAP-EGFP) were successfully constructed. In prostate cancer cell PC-3, pPSAE-PSAP-EGFP expressed more GFP than pPSAP-EGFP and the green fluorescence was also observed in pPSAE-EGFP, which showed that PSA enhancer not only could notably increase the transcription efficiency of PSA promoter but also has modulating ability singly used.
CONCLUSION: The expression efficiency and specificity of gene could be inreased by PSA enhancer/promoter combination which should provide trial evidences for clinical gene therapy of prostate cancer.
PART 2 Study of Hydroxycamptothecin Promoting Apoptosis of Prostate Cancer Cell Line PC-3
OBJECTIVE: To observe the effects of hydroxycamptothecin (HCPT) on the apoptosis of prostate cancer cell line PC-3 and to explore the possible mechanisms.
METHODS: The influence of different concentrations (1×10-1, 1×10-2, 1×10-3, 1×10-4 mg/ml) of HCPT on PC-3 cells proliferation at different time (12, 24, 48 h) was assayed respectively by tetrazolium (MTT) assay. The morphologic changes of apoptosis cells were observed by acridine orange/ethidium bromide dyeing. The DNA of apoptotic cells were analyzed with agarose gel electrophoresis. The apoptosis ratios of HCPT on prostate cacer cells were analyzed with flow cytometry (FCM).
RESULTS: The growth of PC-3 was inhibited by HCPT in time and dose dependence. The values of IC50 were 6.50×10-2 mg/ml (12 h), 2.35×10-2 mg/ml (24h) and 5.31×10-3 mg/ml (48h) respectively. The typical apoptosis cells in fluorescence microscope showed budding phenomena and apoptotic body. And the DNA ladder was observed in ultraviolet light. FCM analysis exhibited that the apotosis ratios of PC-3 cells were distributed in peak shape which reached the maximal point (35.76 %) at 1×10-3 mg/ml.
CONCLUTION: HCPT could suppress PC-3 cells proliferation significantly in different ways. However, the mechanism is not clear and need further studies.
PART 3 Study on the Influence of Hydroxycamptothecin and Smac Gene Regulated by the Prostate Specific Antigen Promoter/Enhancer on PC-3
OBJECTIVE: To construct an eukaryotic expression vector containing Smac gene controlled by human prostate-specific antigen enhancer/promoter and observe the effect of apoptosis induced by recombinant plasmid and low dose hydroxycamptothecin.
METHODS: Construct the recombinant vector with molecular biology technique. After transfection into prostate cancer cell line PC-3 and adding low dose HCPT, the status of cells was observed. And then, the in vitro cellular growth activities were assayed by MTT colorimetry and the apoptosis was measured by flow cytometry. Cellular Smac gene, XIAP gene, and caspase-3 gene expression were determined by reverse transcription-polymerase chain reaction.
RESULTS: The recombinant plasmid of pPSAE-PSAP-Smac was successfully constructed. And only the prostate cancer cell line PC-3 was suppressed after transfection with pPSAE-PSAP-Smac (P<0.05). RT-PCR results showed that Smac mRNA levels were significantly increased (P<0.05) and the expression of Smac regulated by PSA promoter/enhancer was higher comparing to the CMV promoter-driven control vectors (P<0.05). Moreover, we also found that the expression of XIAP in pPSAE-PSAP-Smac group and (HCPT+ pPSAE-PSAP-Smac) group were decreased 67.53% and 76.95% respectively comparing to normal group. However, caspase-3 mRNA levels were as much as 3.94 folds and 4.31 folds comparing to normal control. The growth inhibition rates of PC-3 cells treated with HCPT, pPSAE-PSAP-Smac and (HCPT+ pPSAE-PSAP-Smac) were 25.39%, 30.76% and 70.91% respectively. The cellular apoptosis rates in (HCPT+ pPSAE-PSAP-Smac) group were increased by 22.84 % and 20.02 % (P < 0.01) respectively compared with HCPT group and pPSAE-PSAP-Smac group.
CONCLUTION: An expression vector containing Smac gene based on elements of the PSA gene regulatory sequences has been developed and shown to function in prostate cancer cell lines. The Smac can inhibit IAPs and enhance caspase activity. Even more, it also increases the apoptosis rate companied with low dose HCPT which provides a solid platform for prostate cancer therapy.
目的:利用前列腺特异性抗原(PSA)组织特异性表达的特点,克隆出其上游增强子(PSAE)和启动子(PSAP)片断并对其表达效率和组织特异性表达进行初步研究。
方法:从前列腺癌组织提取基因组DNA,并采用PCR方法分别扩增PSA增强子和启动子序列;利用报告基因pEGFP-1,分别构建含不同调控序列的表达载体;脂质体介导基因转染不同细胞并观察绿色荧光蛋白(GFP)的表达情况。
结果:成功构建质粒pPSAE-EGFP、pPSAP-EGFP、pPSAE-PSAP-EGFP;转染结果显示pPSAE-PSAP-EGFP在前列腺癌细胞PC-3中的荧光强度明显高于pPSAP-EGFP,pPSAE-EGFP同样观察到荧光表达,说明PSA增强子能显著提高PSA启动子的转录能力,并可能具有单独调控基因表达的能力。
结论:PSA增强子和启动子的共同调控可以提高基因表达的有效性和细胞特异性,为前列腺癌的临床基因治疗提供实验依据。羟基喜树碱;;前列腺肿瘤;;凋亡;;化疗
第三部分HCPT联合Smac基因对前列腺癌PC-3细胞的促凋亡作用
目的:利用PSA增强子、启动子构建携带Smac基因、人PSAE/PSAP调控的前列腺特异性真核表达载体,并联合低剂量HCPT,观察其对前列腺癌PC-3细胞的促凋亡作用。
方法:分子生物学方法构建重组真核表达载体;脂质体介导Smac基因转染前列腺癌PC-3细胞,并联合应用低剂量HCPT促进凋亡,台盼蓝染色观察细胞活性,MTT比色分析检测癌细胞抑制率,流式细胞术检测细胞凋亡,逆转录聚合酶链反应检测Smac、XIAP、caspase-3的表达。
结果:成功构建由人PSAE-PSAP调节的含Smac基因的重组载体pPSAE-PSAP-Smac;在转染pPSAE-PSAP-Smac的细胞中,只有PC-3细胞观察到明显抑制(P<0.05)。RT-PCR检测发现转染Smac基因后,Smac mRNA表达水平明显增加(P<0.05),PSAE-PSAP调节的Smac的表达也高于CMV启动子调控的Smac表达(P<0.05)。另外XIAP的表达水平在转染Smac及联合化疗药物后分别降低67.53%和76.95% (P<0.01);而caspase-3 mRNA的含量分别是正常对照的3.94倍和4.31倍(P<0.01)。MTT法检测发现,HCPT和Smac基因对细胞均有抑制作用;HCPT组、pPSAE-PSAP-Smac组、HCPT+ pPSAE-PSAP-Smac组的细胞抑制率分别为25.39%、30.76%、70.91%。流式细胞仪检测显示转染组在加入HCPT后,细胞的凋亡率明显增加,较HCPT组和pPSAE-PSAP-Smac组分别增加22.84 %和20.02 % (P<0.01)。
结论: Smac在癌细胞中的活化表达可以明显增强细胞在刺激信号下的凋亡,其作用机理是通过抑制凋亡抑制蛋白IAPs,解除了对凋亡下游效应半胱氨酸蛋白酶caspase的抑制活性。在与低剂量HCPT联合作用于PC-3细胞时,更能显著增加细胞凋亡率。
PART 1 Construction and Identification of Recombinant Plasmids with Prostate-Specific Antigen Enhancer and Promoter in Gene Expression Regulation
OBJECTIVE: To study the expression efficiency and specificity of prostate specific antigen (PSA) enhancer/promoter in a possible targeted gene therapy scheme for prostate cancer.
METHODS: Genomic DNA was obtained from prostate cancer tissues. PSA enhancer and promoter sequences were amplified using PCR method, then the two fragments were cloned into plasmid pEGFP-1 to construct the expression vectors. After transfecting into different cell lines, the expression status was observed in fluorecent microscopic examination method.
RESULTS: The recombinant plasmids (pPSAE-EGFP, pPSAP-EGFP and pPSAE-PSAP-EGFP) were successfully constructed. In prostate cancer cell PC-3, pPSAE-PSAP-EGFP expressed more GFP than pPSAP-EGFP and the green fluorescence was also observed in pPSAE-EGFP, which showed that PSA enhancer not only could notably increase the transcription efficiency of PSA promoter but also has modulating ability singly used.
CONCLUSION: The expression efficiency and specificity of gene could be inreased by PSA enhancer/promoter combination which should provide trial evidences for clinical gene therapy of prostate cancer.
PART 2 Study of Hydroxycamptothecin Promoting Apoptosis of Prostate Cancer Cell Line PC-3
OBJECTIVE: To observe the effects of hydroxycamptothecin (HCPT) on the apoptosis of prostate cancer cell line PC-3 and to explore the possible mechanisms.
METHODS: The influence of different concentrations (1×10-1, 1×10-2, 1×10-3, 1×10-4 mg/ml) of HCPT on PC-3 cells proliferation at different time (12, 24, 48 h) was assayed respectively by tetrazolium (MTT) assay. The morphologic changes of apoptosis cells were observed by acridine orange/ethidium bromide dyeing. The DNA of apoptotic cells were analyzed with agarose gel electrophoresis. The apoptosis ratios of HCPT on prostate cacer cells were analyzed with flow cytometry (FCM).
RESULTS: The growth of PC-3 was inhibited by HCPT in time and dose dependence. The values of IC50 were 6.50×10-2 mg/ml (12 h), 2.35×10-2 mg/ml (24h) and 5.31×10-3 mg/ml (48h) respectively. The typical apoptosis cells in fluorescence microscope showed budding phenomena and apoptotic body. And the DNA ladder was observed in ultraviolet light. FCM analysis exhibited that the apotosis ratios of PC-3 cells were distributed in peak shape which reached the maximal point (35.76 %) at 1×10-3 mg/ml.
CONCLUTION: HCPT could suppress PC-3 cells proliferation significantly in different ways. However, the mechanism is not clear and need further studies.
PART 3 Study on the Influence of Hydroxycamptothecin and Smac Gene Regulated by the Prostate Specific Antigen Promoter/Enhancer on PC-3
OBJECTIVE: To construct an eukaryotic expression vector containing Smac gene controlled by human prostate-specific antigen enhancer/promoter and observe the effect of apoptosis induced by recombinant plasmid and low dose hydroxycamptothecin.
METHODS: Construct the recombinant vector with molecular biology technique. After transfection into prostate cancer cell line PC-3 and adding low dose HCPT, the status of cells was observed. And then, the in vitro cellular growth activities were assayed by MTT colorimetry and the apoptosis was measured by flow cytometry. Cellular Smac gene, XIAP gene, and caspase-3 gene expression were determined by reverse transcription-polymerase chain reaction.
RESULTS: The recombinant plasmid of pPSAE-PSAP-Smac was successfully constructed. And only the prostate cancer cell line PC-3 was suppressed after transfection with pPSAE-PSAP-Smac (P<0.05). RT-PCR results showed that Smac mRNA levels were significantly increased (P<0.05) and the expression of Smac regulated by PSA promoter/enhancer was higher comparing to the CMV promoter-driven control vectors (P<0.05). Moreover, we also found that the expression of XIAP in pPSAE-PSAP-Smac group and (HCPT+ pPSAE-PSAP-Smac) group were decreased 67.53% and 76.95% respectively comparing to normal group. However, caspase-3 mRNA levels were as much as 3.94 folds and 4.31 folds comparing to normal control. The growth inhibition rates of PC-3 cells treated with HCPT, pPSAE-PSAP-Smac and (HCPT+ pPSAE-PSAP-Smac) were 25.39%, 30.76% and 70.91% respectively. The cellular apoptosis rates in (HCPT+ pPSAE-PSAP-Smac) group were increased by 22.84 % and 20.02 % (P < 0.01) respectively compared with HCPT group and pPSAE-PSAP-Smac group.
CONCLUTION: An expression vector containing Smac gene based on elements of the PSA gene regulatory sequences has been developed and shown to function in prostate cancer cell lines. The Smac can inhibit IAPs and enhance caspase activity. Even more, it also increases the apoptosis rate companied with low dose HCPT which provides a solid platform for prostate cancer therapy.
引文
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