抑癌基因SARI在慢性髓细胞白血病中异常调控分子机制及作用的研究
摘要
目的
SARI基因是近年来发现的一种新型抑癌基因,它在多种正常组织细胞中均有表达,而在许多实体肿瘤中表达水平明显下降。然而其表达异常机制尚不清楚。本课题通过检测慢性髓细胞白血病患者与正常人中SARI基因中的表达水平,以慢性髓细胞白血病细胞系K562为模型,探讨SARI基因在慢性髓细胞白血病中的作用及其表达调节可能的分子机制,为慢性髓细胞白血病基因治疗的研究提供新线索。
方法
(1)初发慢性髓细胞白血病患者中SARI表达水平的研究：46名初发慢性髓细胞白血病患者作为实验组,40名健康受试者作为正常对照组。采集每位患者和健康受试者的外周血,分离单个核细胞,使用实时定量PCR技术检测两组人群中SARI基因的相对表达水平。(2) SARI基因在慢性髓细胞白血病中表达异常分子机制的研究：以慢性髓细胞白血病细胞系K562为研究模型,使用Bcr-Abl抑制剂STI571处理K562细胞,做时间梯度实验和浓度梯度实验。设置浓度梯度：0,0.5,1.5,2.5μM及时间梯度：6,12,24小时。收集各组细胞,用实时定量PCR技术检测各组SARI基因表达情况。使用P13K抑制剂LY294002 (20μM), MEK抑制剂PD98059 (50μM), JAK抑制剂Ag490(501μM)处理K562细胞24小时后收集各组细胞,以未处理K562细胞作为对照组,用实时定量PCR技术检测各组SARI基因表达情况。(3)SARI基因在慢性髓细胞白血病中作用的研究：使用SARI特异性siRNA转染K562细胞：siRNA+转染液+K562细胞为实验组,转染液+K562细胞为Mock对照组,未转染K562细胞为空白对照组。使用750ng SARI特异性siRNA转染K562细胞72小时,用实时定量PCR技术检测K562细胞中SARI基因表达水平,确定其干扰效率。用STI571(2.5μM)分别处理实验组和Mock对照组K562细胞24小时,用流式细胞术检测两组K562细胞凋亡率及STI571处理后两组K562细胞的凋亡率。
结果
1.初发慢性髓细胞白血病患者中SARI表达水平的研究
与正常对照组(n=40)相比,实验组(n=46) SARI基因表达在mRNA水平明显降低,三次实验结果所得数据经过Student's unpaired t-test分析,p<0.001,两组间具有明显的统计学差异。
2. SARI基因在慢性髓细胞白血病中表达异常分子机制的研究2.1 STI571对SARI基因表达的影响
使用STI571(1.5μM)处理K562细胞12小时后SARI基因mRNA表达水平开始增高。在浓度梯度实验中,各组SARI基因表达未显示明显的浓度依赖关系；在时间梯度实验中,各组SARI基因表达显示较明显的时间依赖性,随着处理时间的延长,SARI基因表达逐渐升高。
2.2信号通路抑制剂对SARI基因表达的影响
用MEK抑制剂PD98059处理24小时后,K562细胞中SARI基因1mRNA表达水平高于对照组(p<0.05)；与之相似,用JAK抑制剂Ag490处理24小时后,K562细胞中SARI基因mRNA表达水平高于对照组(p<0.05)；而PI3K抑制剂处理24小时后,K562细胞中SARI基因mRNA表达水平下降。
3. SARI基因在慢性髓细胞白血病中作用的研究
3.1 SARI特异性siRNA干扰效应
与Mock对照组相比,使用SARI特异性siRNA(750ng)转染K562细胞72小时后,SARI基因mRNA表达水平降低了72%(p<0.001)；而空白对照组和Mock对照组SARI基因mRNA表达水平无明显差异(p>0.05)。
3.2 SARI干扰对K562细胞凋亡的影响
使用流式细胞术检测各组凋亡率,与Mock对照组相比,实验组K562细胞凋亡率增加了(1.74±0.30)%,p=0.05)。
3.3 SARI干扰对STI571诱导细胞凋亡的影响
实验组与Mock对照组经过STI571(2.5μM)处理24小时后,使用流式细胞术检测两组凋亡率,与Mock对照组相比,实验组K562细胞凋亡率减少了((7.61±0.16)%,p<0.001)。
结论
慢性髓细胞白血病患者外周血SARI mRNA表达水平降低可能与该疾病的发生发展过程相关联。在慢性髓细胞白血病细胞系K562中,SARI基因表达下调与Bcr-Abl抑制作用有关,而Bcr-Abl下调SARI基因表达可能是通过其下游MEK和JAK信号通路实现的。干扰SARI基因在K562细胞中表达部分降低了STI571诱导的凋亡作用,SARI基因可能参与了STI571诱导细胞凋亡作用。
Objective
SARI (suppressor of activator protein (AP)-1, regulated by (interferon) IFN) is a novel tumor suppressor gene which has been found recently. The constitutive expression of SARI mRNA was detected in multiple lineage-specific normal cells, but not detected in their tumorigenic counterparts. However, the suppression mechanisms of SARI expression are still obscure. This study was purposed to investigate the SARI expression level in patients with chronic myeloid leukemia (CML) and healthy volunteers. This study also aimed to explore the role and the regulation molecular mechanism of SARI in CML-derived cell line K562. The study will provide a new clue for the treatment of CML.
Methods
(1) SARI expression in patients with CML and healthy volunteers:46 patients with CML as the experimental group,40 healthy volunteers as the normal control group. Peripheral blood mononuclear cells (PBMCs) of patients with CML and healthy volunteers were collected. SARI expression in two groups was detected using real-time quantitative PCR. (2) The molecular mechanisms of down-regulation of SARI in CML:in vitro, K562 cells were treated by Bcr-Abl inhibitor STI571. Set the concentration gradient:0,0.5,1.5, 2.5μM and time gradient:6,12,24 hours. Then K562 cells were collected to detect SARI expression using real-time quantitative PCR. In respective experiment, K562 cells were treated by the PI3K inhibitor LY294002 (20μM), MEK inhibitor PD98059 (50μM), JAK inhibitor Ag490 (50μM) for 24 hours. Then the cells were collected to detect SARI expression using real-time quantitative PCR. (3) The role of SARI in CML:K562 cells were transfected with transfection reagent as the Mock control group, non-transfected K562 cells as the control group. K562 cells were transfected with SARI specific siRNA for 72 hours following detection of SARI expression using real-time quantitative PCR. Further, transfected K562 cells were treated by STI571 (2.5μM) for 24 hours. Then K562 cells were collected to detect the apoptosis rate by using flow cytometry.
Results
1. SARI expression in patients with CML and healthy volunteers
Compared with the normal control group (n=40), SARI mRNA expression in the experimental group (n=46) was significantly lower. The data were obtained after three experiments. Student's unpaired t-test was employed to analysis the data. The difference between two groups has statistically significant with p<0.001.
2. The molecular mechanisms of down-regulation of SARI in CML
2.1 The influence of STI571 on SARI expression in K562 cells
In time-course and dose-course study, SARI mRNA expression is enhanced in K562 cells as early as 12 hours after treated with STI571 (1.5μM). And the results show that SARI mRNA expression was up-regulated by STI571 in a time-dependent manner, but not dose-dependent manner at a different time period.
2.2 The influence of signaling pathway inhibitors on SARI expression in K562cells
Treatment with the MEK inhibitor PD98059 for 24 hours, SARI mRNA expression in K562 cells was higher (p<0.001). Similarly, treatment with JAK inhibitor Ag490 for 24 hours, SARI mRNA expression increased in K562 cells (p<0.05). While the PI3K inhibitor LY294002 down-regulated SARI mRNA expression in K562 cells.
3. The role of SARI in CML
3.1 Interference effect of SARI-special siRNA
Compared with the Mock group, SARI mRNA expression in transfected K562 cells was decreased by 72%(p<0.001); while SARI mRNA expression in the control group and the Mock group was no significant difference (p>0.05).
3.2 The influence of SARI-special siRNA on apoptosis of K562 cells
Using flow cytometry to detect the apoptosis rate. Compared with the Mock control group, the apoptosis rate of the transfected K562 cells was increased by (1.74±0.30)% (p=0.05).
3.3 The influence of SARI-special siRNA on STI571-induced apoptosis in K562 cells
Treated with STI571 (2.5μM) for 24 hours, then the apoptosis rate of the transfected group and Mock group were detected by flow cytometry. Compared with the Mock group, the apoptosis rate of the transfected group was reduced by (7.61±0.16)%(p<0.001).
Conclusion
The suppression of SARI expression may be associated with the pathology of CML. Bcr-Abl mediates the down-regulation of SARI mRNA expression in K562 cells. Further, Bcl-Abl down-stream signal pathways, including JAK signal pathway and MEK signal pathway are involved in the down-regulation of SARI mRNA expression in K562 cells. In addition, SARI silencing may decrease the sensitivity of K562 cells against STI571-induced apoptosis.
SARI基因是近年来发现的一种新型抑癌基因,它在多种正常组织细胞中均有表达,而在许多实体肿瘤中表达水平明显下降。然而其表达异常机制尚不清楚。本课题通过检测慢性髓细胞白血病患者与正常人中SARI基因中的表达水平,以慢性髓细胞白血病细胞系K562为模型,探讨SARI基因在慢性髓细胞白血病中的作用及其表达调节可能的分子机制,为慢性髓细胞白血病基因治疗的研究提供新线索。
方法
(1)初发慢性髓细胞白血病患者中SARI表达水平的研究：46名初发慢性髓细胞白血病患者作为实验组,40名健康受试者作为正常对照组。采集每位患者和健康受试者的外周血,分离单个核细胞,使用实时定量PCR技术检测两组人群中SARI基因的相对表达水平。(2) SARI基因在慢性髓细胞白血病中表达异常分子机制的研究：以慢性髓细胞白血病细胞系K562为研究模型,使用Bcr-Abl抑制剂STI571处理K562细胞,做时间梯度实验和浓度梯度实验。设置浓度梯度：0,0.5,1.5,2.5μM及时间梯度：6,12,24小时。收集各组细胞,用实时定量PCR技术检测各组SARI基因表达情况。使用P13K抑制剂LY294002 (20μM), MEK抑制剂PD98059 (50μM), JAK抑制剂Ag490(501μM)处理K562细胞24小时后收集各组细胞,以未处理K562细胞作为对照组,用实时定量PCR技术检测各组SARI基因表达情况。(3)SARI基因在慢性髓细胞白血病中作用的研究：使用SARI特异性siRNA转染K562细胞：siRNA+转染液+K562细胞为实验组,转染液+K562细胞为Mock对照组,未转染K562细胞为空白对照组。使用750ng SARI特异性siRNA转染K562细胞72小时,用实时定量PCR技术检测K562细胞中SARI基因表达水平,确定其干扰效率。用STI571(2.5μM)分别处理实验组和Mock对照组K562细胞24小时,用流式细胞术检测两组K562细胞凋亡率及STI571处理后两组K562细胞的凋亡率。
结果
1.初发慢性髓细胞白血病患者中SARI表达水平的研究
与正常对照组(n=40)相比,实验组(n=46) SARI基因表达在mRNA水平明显降低,三次实验结果所得数据经过Student's unpaired t-test分析,p<0.001,两组间具有明显的统计学差异。
2. SARI基因在慢性髓细胞白血病中表达异常分子机制的研究2.1 STI571对SARI基因表达的影响
使用STI571(1.5μM)处理K562细胞12小时后SARI基因mRNA表达水平开始增高。在浓度梯度实验中,各组SARI基因表达未显示明显的浓度依赖关系；在时间梯度实验中,各组SARI基因表达显示较明显的时间依赖性,随着处理时间的延长,SARI基因表达逐渐升高。
2.2信号通路抑制剂对SARI基因表达的影响
用MEK抑制剂PD98059处理24小时后,K562细胞中SARI基因1mRNA表达水平高于对照组(p<0.05)；与之相似,用JAK抑制剂Ag490处理24小时后,K562细胞中SARI基因mRNA表达水平高于对照组(p<0.05)；而PI3K抑制剂处理24小时后,K562细胞中SARI基因mRNA表达水平下降。
3. SARI基因在慢性髓细胞白血病中作用的研究
3.1 SARI特异性siRNA干扰效应
与Mock对照组相比,使用SARI特异性siRNA(750ng)转染K562细胞72小时后,SARI基因mRNA表达水平降低了72%(p<0.001)；而空白对照组和Mock对照组SARI基因mRNA表达水平无明显差异(p>0.05)。
3.2 SARI干扰对K562细胞凋亡的影响
使用流式细胞术检测各组凋亡率,与Mock对照组相比,实验组K562细胞凋亡率增加了(1.74±0.30)%,p=0.05)。
3.3 SARI干扰对STI571诱导细胞凋亡的影响
实验组与Mock对照组经过STI571(2.5μM)处理24小时后,使用流式细胞术检测两组凋亡率,与Mock对照组相比,实验组K562细胞凋亡率减少了((7.61±0.16)%,p<0.001)。
结论
慢性髓细胞白血病患者外周血SARI mRNA表达水平降低可能与该疾病的发生发展过程相关联。在慢性髓细胞白血病细胞系K562中,SARI基因表达下调与Bcr-Abl抑制作用有关,而Bcr-Abl下调SARI基因表达可能是通过其下游MEK和JAK信号通路实现的。干扰SARI基因在K562细胞中表达部分降低了STI571诱导的凋亡作用,SARI基因可能参与了STI571诱导细胞凋亡作用。
Objective
SARI (suppressor of activator protein (AP)-1, regulated by (interferon) IFN) is a novel tumor suppressor gene which has been found recently. The constitutive expression of SARI mRNA was detected in multiple lineage-specific normal cells, but not detected in their tumorigenic counterparts. However, the suppression mechanisms of SARI expression are still obscure. This study was purposed to investigate the SARI expression level in patients with chronic myeloid leukemia (CML) and healthy volunteers. This study also aimed to explore the role and the regulation molecular mechanism of SARI in CML-derived cell line K562. The study will provide a new clue for the treatment of CML.
Methods
(1) SARI expression in patients with CML and healthy volunteers:46 patients with CML as the experimental group,40 healthy volunteers as the normal control group. Peripheral blood mononuclear cells (PBMCs) of patients with CML and healthy volunteers were collected. SARI expression in two groups was detected using real-time quantitative PCR. (2) The molecular mechanisms of down-regulation of SARI in CML:in vitro, K562 cells were treated by Bcr-Abl inhibitor STI571. Set the concentration gradient:0,0.5,1.5, 2.5μM and time gradient:6,12,24 hours. Then K562 cells were collected to detect SARI expression using real-time quantitative PCR. In respective experiment, K562 cells were treated by the PI3K inhibitor LY294002 (20μM), MEK inhibitor PD98059 (50μM), JAK inhibitor Ag490 (50μM) for 24 hours. Then the cells were collected to detect SARI expression using real-time quantitative PCR. (3) The role of SARI in CML:K562 cells were transfected with transfection reagent as the Mock control group, non-transfected K562 cells as the control group. K562 cells were transfected with SARI specific siRNA for 72 hours following detection of SARI expression using real-time quantitative PCR. Further, transfected K562 cells were treated by STI571 (2.5μM) for 24 hours. Then K562 cells were collected to detect the apoptosis rate by using flow cytometry.
Results
1. SARI expression in patients with CML and healthy volunteers
Compared with the normal control group (n=40), SARI mRNA expression in the experimental group (n=46) was significantly lower. The data were obtained after three experiments. Student's unpaired t-test was employed to analysis the data. The difference between two groups has statistically significant with p<0.001.
2. The molecular mechanisms of down-regulation of SARI in CML
2.1 The influence of STI571 on SARI expression in K562 cells
In time-course and dose-course study, SARI mRNA expression is enhanced in K562 cells as early as 12 hours after treated with STI571 (1.5μM). And the results show that SARI mRNA expression was up-regulated by STI571 in a time-dependent manner, but not dose-dependent manner at a different time period.
2.2 The influence of signaling pathway inhibitors on SARI expression in K562cells
Treatment with the MEK inhibitor PD98059 for 24 hours, SARI mRNA expression in K562 cells was higher (p<0.001). Similarly, treatment with JAK inhibitor Ag490 for 24 hours, SARI mRNA expression increased in K562 cells (p<0.05). While the PI3K inhibitor LY294002 down-regulated SARI mRNA expression in K562 cells.
3. The role of SARI in CML
3.1 Interference effect of SARI-special siRNA
Compared with the Mock group, SARI mRNA expression in transfected K562 cells was decreased by 72%(p<0.001); while SARI mRNA expression in the control group and the Mock group was no significant difference (p>0.05).
3.2 The influence of SARI-special siRNA on apoptosis of K562 cells
Using flow cytometry to detect the apoptosis rate. Compared with the Mock control group, the apoptosis rate of the transfected K562 cells was increased by (1.74±0.30)% (p=0.05).
3.3 The influence of SARI-special siRNA on STI571-induced apoptosis in K562 cells
Treated with STI571 (2.5μM) for 24 hours, then the apoptosis rate of the transfected group and Mock group were detected by flow cytometry. Compared with the Mock group, the apoptosis rate of the transfected group was reduced by (7.61±0.16)%(p<0.001).
Conclusion
The suppression of SARI expression may be associated with the pathology of CML. Bcr-Abl mediates the down-regulation of SARI mRNA expression in K562 cells. Further, Bcl-Abl down-stream signal pathways, including JAK signal pathway and MEK signal pathway are involved in the down-regulation of SARI mRNA expression in K562 cells. In addition, SARI silencing may decrease the sensitivity of K562 cells against STI571-induced apoptosis.
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