Mcl-1反义核酸对肝癌HepG2细胞的生物学特性的影响
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摘要
目的:
筛选Bcl-2家族ASODNs对消化系肿瘤HepG2、LOVO、MGC-803细胞增殖抑制和促凋亡作用较强的成员。将筛选出的成员Mcl-1 ASODN转染肝癌HepG2细胞,并检测该反义核酸对肝癌细胞的部分生物学功能(增殖抑制、促凋亡、提高肝癌对常用化疗药物的敏感性、基因表达)的影响,为基于Mcl-1为靶标的肝癌治疗提供实验基础。
方法:
第一部分筛选对肝癌、胃癌、结肠癌细胞生长抑制作用较强的Bcl-2家族成员ASODN
1.WST-8法筛选出对肝癌、胃癌、结肠癌细胞增殖抑制作用较强的成员
2.流式细胞术筛选出对肝癌、结肠癌细胞促凋亡作用较强的成员
第二部分Mcl-1 ASODN对肝癌细胞生物学特性的影响
1.WST-8法检测Mcl-1 ASODN对肝癌细胞的增殖抑制作用
2.Realtime PCR检测Mcl-1 ASODN对肝癌细胞Mcl-1 mRNA的影响
3.Hoechst 33258染色观察Mcl-1 ASODN对肝癌细胞形态的影响
4.PI单染流式细胞术检测Mcl-1 ASODN对肝癌细胞周期的影响
5.PI-Annexin V双染流式细胞术检测Mcl-1 ASODN对肝癌细胞凋亡的影响
6.WST-8法检测Mcl-1 ASODN对肝癌细胞化疗(顺铂和表柔比星)敏感性的影响
结果:
第一部分筛选对肝癌、胃癌、结肠癌细胞生长抑制作用较强的bcl-2家族成员ASODN
1.在Bcl-2家族各成员的ASODNs中,Bcl-xl ASODN和Mcl-1 ASODN对肝癌,结肠癌及胃癌细胞的增殖抑制作用最强
2.在Bcl-2家族各成员的ASODNs中,Bcl-xl ASODN和Mcl-1 ASODN对肝癌和结肠癌细胞的促凋亡作用最强
第二部分Mcl-1 ASODN对肝癌细胞生物学特性的影响
1.Mcl-1 ASODN作用于肝癌细胞48h后,Mcl-1 ASODN能有效下调肝癌细胞中的mcl-1 mRNA的表达,且0.25μmol/L的浓度就开始起作用,随着浓度的升高,下调作用就越强,表达抑制率可高达80%
2.Mcl-1 ASODN作用于肝癌细胞48h后,能有效抑制肝癌细胞的增殖,与随机寡核苷酸对照组(RODN)相比,差异具有统计学意义,随着浓度的升高,增殖抑制率越高,0.25μmol/L时增殖抑制率为29.66%,1.0μmol/L时为52.36%
3.Mcl-1 ASODN作用于肝癌细胞48h后,Hoechst 33258染色可以观察到细胞出现明显的细胞核碎裂,边集,凋亡小体形成等凋亡形态学的改变
4.各组药物作用于肝癌细胞48h后,与空白对照(control)组相比,Mcl-1ASODN组S期细胞明显增多,出现明显的S期阻滞。
5.各组药物作用于肝癌细胞48h后,与control组相比,Mcl-1 ASODN组早期凋亡率明显增高,凋亡率达13.6%;而RODN组早期凋亡率只有2.8%
6.药敏实验结果
(1)单独顺铂IC50为27.5μg/mL,顺铂与0.25μmol/L Mcl-1 ASODN联用后,IC50为7.26μg/mL,IC50提高了3.79倍,利用金正均Q概率和法得出Q值＞1.15,说明它们之间具有协同作用
(2)单独表柔比星IC50为1.54μg/mL,表柔比星与0.25μmol/L Mcl-1 ASODN联用后,IC50为0.48μg/mL,IC50提高了3.21倍,利用金正均Q概率和法得出Q值＜1.15,说明它们之间只具有相加作用。
结论:
1.在HepG2、MGC-803和LOVO细胞中,均显示Bcl-xl ASODN和Mcl-1ASODN的增殖抑制作用和促凋亡作用较强,Bcl-2 ASOND次之(在HepG2细胞中无作用),Bcl-w ASODN和A1 ASODN作用较弱
2.Mcl-1 ASODN能有效抑制肝癌细胞mcl-1 mRNA的表达,并抑制肝癌细胞增殖,将其阻滞在S期,并促进其凋亡
3.Mcl-1 ASODN能提高肝癌细胞对顺铂和表柔比星的敏感性
Objective:
To screen out the strongest member of Bcl-2 family ASODNs,which inhibit the proliferation and induce apoptosis of digestive tract carcinoma cell lines(HepG2 LOVO and MGC-803 cells).To transfect the Mcl-1 ASODN into hepatocellular carcinoma HepG2 cells and test the effect of the ASODN on several biological fuctions(inhibit proliferation,induce apoptosis,sensitize HepG2 cells to chemotherapeutic drugs and gene expression) of HepG2 cells,to provide a new target.
Methods
PartⅠScreen out the strongest one of Bcl-2 family member ASODNs inhibiting the growth of hepatocellular carcinoma,gastric cancer and colon cancer.
1.Screen out the strongest one inhibiting the proliferation of hepatocellular carcinoma,gastric cancer and colon cancer cell lines by WST-8 test.
2.Screen out the strongest one inducing apoptosis of hepatocellular carcinoma and colon cancer cell lines by flow cytometry.
PartⅡThe effect of mcl-1 ASODN on the biological function of hepatocellular carcinoma cells
1.Test the effect of Mcl-1 ASODN on inhibiting proliferation of hepatocellular carcinoma cells by WST-8 test.
2.Test the effect of Mcl-1 ASODN on Mcl-1 mRNA of hepatocellular carcinoma cells by realtime PCR.
3.Observe the morphology of apoptosis of hepatocellular carcinoma cells by Hoechst 33258 staining
4.Test the effect of Mcl-1 ASODN on cell cycle of hepatocellular carcinoma cells by flow cytometry.
5.Test the effect of Mcl-1 ASODN on apoptosis of hepatocellular carinoma cells by flow cytometry.
6.Test the effect of Mcl-1 ASODN on sensitizing hepatocellular carcinoma cells to chemotherapeutic drugs(cisplatin and epirubicin) by WST-8 test.
Results
PartⅠScreen out the strongest one of Bcl-2 family member ASODNs inhibiting the growth of hepatocellular carcinoma,gastric cancer and colon cancer.
1.Among all of Bcl-2 family member ASODNs,Bcl-xl ASODN and Mcl-1 ASODN are the strongest members which inhibit the proliferation of hepatocellular carciona,colon cancer and gastric cancer cell lines.
2.Among all of Bcl-2 family member ASODNs,Bcl-xl ASODN and Mcl-1 ASODN are the strongest members which induce apopotosis of hepatocellular carciona and colon cancer
PartⅡThe effect of Mcl-1 ASODN on the biological function of hepatocellular carcinoma cells
1.After Mcl-1 ASODN was transfected into hepatocellular carcinoma cells 48h, it can inhibit the expression of mcl-1 mRNA effectively,the low effective concentration is 0.25μmol/L,when the concentration is higher,the inhibitory rates is more higher,it can reach up to 80%.
2.After Mcl-1 ASODN was transfected into hepatocellular carcinoma cells 48h, compared with random Oligodeoxynuleotides control(RODN) group,the difference is of statistic significance,when the concentration is higher,the inhibitory rate is higher,when the concentration is 0.25μmol/L,the inhibitory rate is 29.66%,when the concentration is 1.0μmol/L,the inhibitory rate is 52.36%.
3.After Mcl-1 ASODN was transfected into hepatocellular carcinoma cells 48h, apoptotic morphological alterations,such as chromatin condensation and apoptotic bodies were also observed by staining with Hoechst33258 under the fluorescence microscope.
4.Compared with control group,the cells in s phase increase obviously,resulted in cell cycle arrest at s phase
5.Compared with control group,the apoptotic rates of Mcl-1 ASODN group increases,it can reach up to 13.6%,the difference is of statistical significance; but the apoptotic rates of RODN group is only 2.8%,the difference is of no statistical significance.
6.The results of sensitizing hepatocellular carcinoma cells to chemotherapeutic drugs
(1) The IC50 of single cisplatin is 27.5μg/mL,after combined with Mcl-1 ASODN,the IC50 is 7.26μg/mL,it is 3.79 times of single cisplatin,and their combined effect is of synergism.
(2) The IC50 of single epirubicin is 1.54μg/mL,after combined with Mcl-1 ASODN,the IC50 is 0.48μg/mL,the IC50 is 3.21 times of single epirubicin, and their combined effect is additional
Conclusion
1.In HepG2,MGC-803 and LOVO cells,they all display that Bcl-xl ASODN and Mcl-1 ASODN are the strongest members which inhibit the proliferation and induce apoptosis,Bcl-2 ASODN is weaker(except in HepG2 cells),Bcl-w and A1 ASODN is the weakest one.
2.Mcl-1 ASODN can inhibit the expression the mcl-1 mRNA effectively,inhibit the proliferation of hepatocellular carcinoma cells,resulted in cell cycle arrest at s phase,and induce apoptosis.
3.Mcl-1 ASODN can sensitize hepatocellular carcinoma cells to cisplatin and epirubicin
筛选Bcl-2家族ASODNs对消化系肿瘤HepG2、LOVO、MGC-803细胞增殖抑制和促凋亡作用较强的成员。将筛选出的成员Mcl-1 ASODN转染肝癌HepG2细胞,并检测该反义核酸对肝癌细胞的部分生物学功能(增殖抑制、促凋亡、提高肝癌对常用化疗药物的敏感性、基因表达)的影响,为基于Mcl-1为靶标的肝癌治疗提供实验基础。
方法:
第一部分筛选对肝癌、胃癌、结肠癌细胞生长抑制作用较强的Bcl-2家族成员ASODN
1.WST-8法筛选出对肝癌、胃癌、结肠癌细胞增殖抑制作用较强的成员
2.流式细胞术筛选出对肝癌、结肠癌细胞促凋亡作用较强的成员
第二部分Mcl-1 ASODN对肝癌细胞生物学特性的影响
1.WST-8法检测Mcl-1 ASODN对肝癌细胞的增殖抑制作用
2.Realtime PCR检测Mcl-1 ASODN对肝癌细胞Mcl-1 mRNA的影响
3.Hoechst 33258染色观察Mcl-1 ASODN对肝癌细胞形态的影响
4.PI单染流式细胞术检测Mcl-1 ASODN对肝癌细胞周期的影响
5.PI-Annexin V双染流式细胞术检测Mcl-1 ASODN对肝癌细胞凋亡的影响
6.WST-8法检测Mcl-1 ASODN对肝癌细胞化疗(顺铂和表柔比星)敏感性的影响
结果:
第一部分筛选对肝癌、胃癌、结肠癌细胞生长抑制作用较强的bcl-2家族成员ASODN
1.在Bcl-2家族各成员的ASODNs中,Bcl-xl ASODN和Mcl-1 ASODN对肝癌,结肠癌及胃癌细胞的增殖抑制作用最强
2.在Bcl-2家族各成员的ASODNs中,Bcl-xl ASODN和Mcl-1 ASODN对肝癌和结肠癌细胞的促凋亡作用最强
第二部分Mcl-1 ASODN对肝癌细胞生物学特性的影响
1.Mcl-1 ASODN作用于肝癌细胞48h后,Mcl-1 ASODN能有效下调肝癌细胞中的mcl-1 mRNA的表达,且0.25μmol/L的浓度就开始起作用,随着浓度的升高,下调作用就越强,表达抑制率可高达80%
2.Mcl-1 ASODN作用于肝癌细胞48h后,能有效抑制肝癌细胞的增殖,与随机寡核苷酸对照组(RODN)相比,差异具有统计学意义,随着浓度的升高,增殖抑制率越高,0.25μmol/L时增殖抑制率为29.66%,1.0μmol/L时为52.36%
3.Mcl-1 ASODN作用于肝癌细胞48h后,Hoechst 33258染色可以观察到细胞出现明显的细胞核碎裂,边集,凋亡小体形成等凋亡形态学的改变
4.各组药物作用于肝癌细胞48h后,与空白对照(control)组相比,Mcl-1ASODN组S期细胞明显增多,出现明显的S期阻滞。
5.各组药物作用于肝癌细胞48h后,与control组相比,Mcl-1 ASODN组早期凋亡率明显增高,凋亡率达13.6%;而RODN组早期凋亡率只有2.8%
6.药敏实验结果
(1)单独顺铂IC50为27.5μg/mL,顺铂与0.25μmol/L Mcl-1 ASODN联用后,IC50为7.26μg/mL,IC50提高了3.79倍,利用金正均Q概率和法得出Q值＞1.15,说明它们之间具有协同作用
(2)单独表柔比星IC50为1.54μg/mL,表柔比星与0.25μmol/L Mcl-1 ASODN联用后,IC50为0.48μg/mL,IC50提高了3.21倍,利用金正均Q概率和法得出Q值＜1.15,说明它们之间只具有相加作用。
结论:
1.在HepG2、MGC-803和LOVO细胞中,均显示Bcl-xl ASODN和Mcl-1ASODN的增殖抑制作用和促凋亡作用较强,Bcl-2 ASOND次之(在HepG2细胞中无作用),Bcl-w ASODN和A1 ASODN作用较弱
2.Mcl-1 ASODN能有效抑制肝癌细胞mcl-1 mRNA的表达,并抑制肝癌细胞增殖,将其阻滞在S期,并促进其凋亡
3.Mcl-1 ASODN能提高肝癌细胞对顺铂和表柔比星的敏感性
Objective:
To screen out the strongest member of Bcl-2 family ASODNs,which inhibit the proliferation and induce apoptosis of digestive tract carcinoma cell lines(HepG2 LOVO and MGC-803 cells).To transfect the Mcl-1 ASODN into hepatocellular carcinoma HepG2 cells and test the effect of the ASODN on several biological fuctions(inhibit proliferation,induce apoptosis,sensitize HepG2 cells to chemotherapeutic drugs and gene expression) of HepG2 cells,to provide a new target.
Methods
PartⅠScreen out the strongest one of Bcl-2 family member ASODNs inhibiting the growth of hepatocellular carcinoma,gastric cancer and colon cancer.
1.Screen out the strongest one inhibiting the proliferation of hepatocellular carcinoma,gastric cancer and colon cancer cell lines by WST-8 test.
2.Screen out the strongest one inducing apoptosis of hepatocellular carcinoma and colon cancer cell lines by flow cytometry.
PartⅡThe effect of mcl-1 ASODN on the biological function of hepatocellular carcinoma cells
1.Test the effect of Mcl-1 ASODN on inhibiting proliferation of hepatocellular carcinoma cells by WST-8 test.
2.Test the effect of Mcl-1 ASODN on Mcl-1 mRNA of hepatocellular carcinoma cells by realtime PCR.
3.Observe the morphology of apoptosis of hepatocellular carcinoma cells by Hoechst 33258 staining
4.Test the effect of Mcl-1 ASODN on cell cycle of hepatocellular carcinoma cells by flow cytometry.
5.Test the effect of Mcl-1 ASODN on apoptosis of hepatocellular carinoma cells by flow cytometry.
6.Test the effect of Mcl-1 ASODN on sensitizing hepatocellular carcinoma cells to chemotherapeutic drugs(cisplatin and epirubicin) by WST-8 test.
Results
PartⅠScreen out the strongest one of Bcl-2 family member ASODNs inhibiting the growth of hepatocellular carcinoma,gastric cancer and colon cancer.
1.Among all of Bcl-2 family member ASODNs,Bcl-xl ASODN and Mcl-1 ASODN are the strongest members which inhibit the proliferation of hepatocellular carciona,colon cancer and gastric cancer cell lines.
2.Among all of Bcl-2 family member ASODNs,Bcl-xl ASODN and Mcl-1 ASODN are the strongest members which induce apopotosis of hepatocellular carciona and colon cancer
PartⅡThe effect of Mcl-1 ASODN on the biological function of hepatocellular carcinoma cells
1.After Mcl-1 ASODN was transfected into hepatocellular carcinoma cells 48h, it can inhibit the expression of mcl-1 mRNA effectively,the low effective concentration is 0.25μmol/L,when the concentration is higher,the inhibitory rates is more higher,it can reach up to 80%.
2.After Mcl-1 ASODN was transfected into hepatocellular carcinoma cells 48h, compared with random Oligodeoxynuleotides control(RODN) group,the difference is of statistic significance,when the concentration is higher,the inhibitory rate is higher,when the concentration is 0.25μmol/L,the inhibitory rate is 29.66%,when the concentration is 1.0μmol/L,the inhibitory rate is 52.36%.
3.After Mcl-1 ASODN was transfected into hepatocellular carcinoma cells 48h, apoptotic morphological alterations,such as chromatin condensation and apoptotic bodies were also observed by staining with Hoechst33258 under the fluorescence microscope.
4.Compared with control group,the cells in s phase increase obviously,resulted in cell cycle arrest at s phase
5.Compared with control group,the apoptotic rates of Mcl-1 ASODN group increases,it can reach up to 13.6%,the difference is of statistical significance; but the apoptotic rates of RODN group is only 2.8%,the difference is of no statistical significance.
6.The results of sensitizing hepatocellular carcinoma cells to chemotherapeutic drugs
(1) The IC50 of single cisplatin is 27.5μg/mL,after combined with Mcl-1 ASODN,the IC50 is 7.26μg/mL,it is 3.79 times of single cisplatin,and their combined effect is of synergism.
(2) The IC50 of single epirubicin is 1.54μg/mL,after combined with Mcl-1 ASODN,the IC50 is 0.48μg/mL,the IC50 is 3.21 times of single epirubicin, and their combined effect is additional
Conclusion
1.In HepG2,MGC-803 and LOVO cells,they all display that Bcl-xl ASODN and Mcl-1 ASODN are the strongest members which inhibit the proliferation and induce apoptosis,Bcl-2 ASODN is weaker(except in HepG2 cells),Bcl-w and A1 ASODN is the weakest one.
2.Mcl-1 ASODN can inhibit the expression the mcl-1 mRNA effectively,inhibit the proliferation of hepatocellular carcinoma cells,resulted in cell cycle arrest at s phase,and induce apoptosis.
3.Mcl-1 ASODN can sensitize hepatocellular carcinoma cells to cisplatin and epirubicin
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