Stat3信号转导通路调控宫颈癌细胞系增殖凋亡的体外研究
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摘要
目的:研究宫颈癌细胞系中Stat3、p-Stat3、Cyclin D1与Survivin蛋白的表达,及p-Stat3与CyclinD1、Survivin表达的关系,应用该通路的特异性阻滞剂AG490作用于宫颈癌细胞系,观察其对宫颈癌细胞增殖、凋亡及细胞周期的影响,检测JAK2、p-Stat3、Stat3蛋白表达及与下游靶基因产物CyclinD1、Survivin蛋白表达的关系,探讨Stat3信号传导通路在宫颈癌发生发展中的调控机制,寻找宫颈癌早期诊治的标志物,进一步分析通过药物阻断Stat3信号通路在治疗宫颈癌中的作用。
方法:1.对人宫颈癌细胞系Hela细胞进行体外培养。2.采用Western-blot技术检测宫颈癌细胞系中Stat3、p-Stat3蛋白及其下游靶基因产物CyclinD1、Survivin蛋白的表达。3.用不同浓度AG490处理Hela细胞,作为实验组,将加入无血清培养基的Hela细胞作为对照组,同时设不接种细胞的空白对照组。4.MTT法检测不同浓度(25μmol/L、50μmol/L、100μmol/L)AG490对Hela细胞作用24h、48h及72h后细胞的增殖情况。5.流式细胞技术检测加入25μmol/L、50μmol/L、100μmol/LAG490作用48h后细胞周期的变化。6.流式细胞技术检测加入25μmol/L、50μmol/L、100μmol/LAG490对Hela细胞作用24h、48h及72h后细胞的凋亡情况。7.Western Blot法检测25μmol/L、50μmol/L、100μmol/L AG490作用48h后,Hela细胞JAK2、Stat3、p-Stat3表达情况及下游靶基因产物细胞周期素(CyclinD1)及生存素(Survivin)的表达水平,并分析p-Stat3与CyclinD1及Survivin表达的相关性。
结果:1.宫颈癌细胞系Hela细胞中存在着组成性激活的Stat3信号。2.p-Stat3与CyclinD1及Survivin表达趋势一致。3.Hela细胞经AG490处理后,细胞增殖水平下降,有浓度依赖效应。AG490处理后48小时,各浓度组与对照组比较有统计学差异(P＜0.01)。AG490加入浓度在25μmol/L～100μmol/L范围内时,AG490浓度越高,其对Hela细胞增殖抑制效应越强(P＜0.05)。对AG490处理Hela细胞不同时间长度后细胞增殖状态的检测表明,25μmol/L AG490处NHela细胞24小时就开始表现出增殖抑制效应,72小时后表现出明显的抑制效应,细胞生存率持续下降(P＜0.05),有时间依赖性。4.阻断Stat3信号传导通路使宫颈癌细胞系细胞周期阻滞。50μmol/L AG490作用细胞48h后G0/G1期从(65.37±1.1 8)%上升至(74.67±3.13)%(P＜0.05),S期从(22.54±0.78)%下降至(17.45±1.45)%(P＜0.05),细胞基本阻滞于G0/G1期。同时,AG490对Hela细胞周期的阻滞作用有剂量依赖性。5.AG490促进宫颈癌细胞系凋亡。25umol/L AG490作用于Hela细胞24h后,流式细胞检测结果显示细胞凋亡率为(8.43±2.57)%。25μmol/L、50μmol/L、100μmol/LAG490处理Hela细胞48h后,凋亡率分别为(13.58±1.42)%,(23.44±1.55)%,(31.05±2.09)%,与对照组检测结果(2.99±0.75)%比较有统计学差异(P＜0.05),且各浓度组之间比较有统计学差异(F=131.15,P＜0.05),表明AG490促进Hela细胞凋亡并有浓度依赖效应。6.不同浓度AG490处理细胞后,Western blot检测发现各处理组JAK2及p-Stat3蛋白表达水平降低(P＜0.05),Stat3蛋白表达与对照组之间变化不大(P＞0.05)。7.不同浓度AG490作用于Hela细胞后Stat3信号通路下游靶基因产物CyclinD1及Survivin表达下调。经Pearson's相关性分析显示,在宫颈癌细胞中p-Stat3与CyclinD1及Survivin表达呈线性相关(r=0.901,P＜0.01;r=0.844,P＜0.01),提示CyclinD1及Survivin作为STAT3信号转导通路的重要下游基因产物,参与了Hela细胞的细胞周期、增殖及凋亡的调控。
结论:1.从蛋白水平证实宫颈癌中存在着组成性激活的Stat3信号通路。2.AG490可以特异地阻断Hela细胞中组成性激活的Stat3信号通路。3.AG490阻断Stat3转导通路后,宫颈癌细胞系Hela细胞的G0/G1期比例明显增高,S期细胞比率降低,细胞周期阻滞,细胞的增殖水平显著下降,该效应主要是通过调节Stat3信号通路下游靶基因产物CyclinD1来实现。4.AG490能够抑制宫颈癌细胞的增殖,促进细胞凋亡,主要是通过下调Stat3信号通路下游产物Survivin来实现。5.AG490可使JAK2,p-Stat3及下游靶基因产物CyclinD1、Survivin表达下调,同时p-Stat3与CyclinD1及Survivin表达呈正相关。6.Stat3信号转导通路通过调控下游靶基因产物CyclinD1、Survivin来促进人宫颈癌细胞系的细胞周期进行,加快细胞增殖,抑制细胞凋亡,参与宫颈癌的发生发展,通过阻断该通路来进行分子靶向治疗。7.p-Stat3蛋白可作为宫颈癌早期诊断、观察病情的一种生物学指标。
Objective: To study the expressions of Stat3, p-Stat3, CyclinD1 and Survivin in cervical cancer cell lines. The correlation between p-Stat3, CyclinD1 and Survivin were also observed. After treated by AG490 (a selective inhibitor of JAK2), we studied the relationship between the cervical cancer cell life cycle and the expressions of JAK2, Stat3, p-Stat3, CyclinD1 and Survivin protein. The potential mechanism of Stat3 signal transduction pathway in controlling the cancer cell transformation from G1 to S stage, proliferation and apoptosis was analysed to search for new biologic marker for diagnosis and therapy in human cervical cancer at early process. Finaly, the regulating mechanism of drug to occurre and develop cervical cancer by blocking Stat3 signal pathway was tried to explain.
Methods: 1.Hela cells were cultured in vitro. 2. Western-blot technique was used for detecting the protein expressions of Stat3, p-Stat3, and their downstream target gene product CyclinD1 and Survivin in human cervical cancer cell lines. 3. Hela cells were treated with different AG490 as experiment group, and the serum-free medium was used as control group. The blank control group did not plant cells at all. 4. Cell proliferation was detected by MTT assay. 5. Flow cytometry was applied to analyze the cell cycle and apoptosis. 6. The expressions of phosphorylation-JAK2 (JAK2), phosphorylation-Stat3 (p-Stat3), Stat3, CyclinD1 and Survivin were measured by Western blot after different AG490 treating. The correlation between p-Stat3, CyclinD1 and Survivin were also investigated.
Results: 1. Constitutively activated Stat3 signal existed in human cervical cancer cell lines. 2. Western Blotting showed that the vary tendency of CyclinD1 and Survivin expressions was similar to that of p-Stat3. 3. Proliferation of Hela cells decreased by concentration-depended manner after treatment with AG490. Detected at different doses after AG490 treating for 48h, the inhibition rate increased when AG490 concentration raised from 25 to 100μmol/L (P < 0.05). Three doses of AG490 treated expenriment groups have statistic meaning compared with control group(P < 0.01). Detected inhibition rate at different time after treatment with AG490 showed that some inhibition effects were found after 24h. The effect became obvious after treatment about 72h and cell survival rate decreased constantly (P < 0.05). 4. Stat3 signal transduction pathway contributes to the change of Hela cell from G1 phase to S phase. It was found that the cell proportion of G0/G1 phase increased from (65.37±1.18)% to (74.67±3.13)% (P < 0.05), and S phase decreased from (22.54±0.78)% to (17.45±1.45)% (P < 0.05). AG490 blocked Hela cell life cycle by concentration-dependent manner. 5. AG490 promoted the apoptosis of Hela cells. AG490 was used to treat Hela cells for 24h, and the percentage of apoptotic cells raised from (1.51±0.03)% to (8.43±2.57)%(P < 0.05). Detected apoptosis at 25μmol/L、50μmol/L、100μmol/L after AG490 treating 48h, the apoptosis rate was determined as (13.58±1.42)%, (23.44±1.55)%, (31.05±2.09)% respectively. Comparing the difference between control group and experiment groups have statistical significance (P < 0.05). Moreover, apoptosis rate differece of Hela cells with various concentration AG490 treating is significant (P < 0.05), which indicate AG490 induce Hela cells apoptosis with a concentration-dependent manner. 6. The expressions of JAK2 and p-Stat3 declined significantly (P < 0.05), but Stat3 had no obvious change after different concentration AG490 treating. 7. The expressions of CyclinD1 and Survivin decreased in Hela cells after AG490 treatment. Pearson's correlation analysis was used to analyse the correlation and variability of expressions of p-Stat3, CyclinD1 and Survivin in cervical cancer cell line. The expressions of p-Stat3 and CyclinD1 exhibit linear correlation (r=0.901, P < 0.01). Moreover, p-Stat3 and Survivin have the similar linear correlation (r=0.844, P < 0.01).
Conclusion: 1. The study of protein level confirmed that constitutive activation of Stat3 signal pathway exists in Hela cells. 2. AG490 can block Stat3 signal pathway selectively. 3. Blocking Stat3 pathway by AG490 in Hela cells, the cell cycle were changed, percentage of G0/G1 phase increased and S phase declined. Cell proliferation was also inhibited. The intrinsic mechanism is that AG490 downregulate the expression of CyclinD1. 4. AG490 inhibits Hela cells proliferation and promotes cell apoptosis through declining the expression of Survivin. 5. As targeted gene product, CyclinD1 and Survivin participate in the regulation of cell cycle, proliferation and apoptosis. 6. Stat3 signal pathway could be a novel target of cervical cancer therapy. 7. p-Stat3 can be a biologic marker for diagnosis and therapy in human cervical cancer at early process.
方法:1.对人宫颈癌细胞系Hela细胞进行体外培养。2.采用Western-blot技术检测宫颈癌细胞系中Stat3、p-Stat3蛋白及其下游靶基因产物CyclinD1、Survivin蛋白的表达。3.用不同浓度AG490处理Hela细胞,作为实验组,将加入无血清培养基的Hela细胞作为对照组,同时设不接种细胞的空白对照组。4.MTT法检测不同浓度(25μmol/L、50μmol/L、100μmol/L)AG490对Hela细胞作用24h、48h及72h后细胞的增殖情况。5.流式细胞技术检测加入25μmol/L、50μmol/L、100μmol/LAG490作用48h后细胞周期的变化。6.流式细胞技术检测加入25μmol/L、50μmol/L、100μmol/LAG490对Hela细胞作用24h、48h及72h后细胞的凋亡情况。7.Western Blot法检测25μmol/L、50μmol/L、100μmol/L AG490作用48h后,Hela细胞JAK2、Stat3、p-Stat3表达情况及下游靶基因产物细胞周期素(CyclinD1)及生存素(Survivin)的表达水平,并分析p-Stat3与CyclinD1及Survivin表达的相关性。
结果:1.宫颈癌细胞系Hela细胞中存在着组成性激活的Stat3信号。2.p-Stat3与CyclinD1及Survivin表达趋势一致。3.Hela细胞经AG490处理后,细胞增殖水平下降,有浓度依赖效应。AG490处理后48小时,各浓度组与对照组比较有统计学差异(P＜0.01)。AG490加入浓度在25μmol/L～100μmol/L范围内时,AG490浓度越高,其对Hela细胞增殖抑制效应越强(P＜0.05)。对AG490处理Hela细胞不同时间长度后细胞增殖状态的检测表明,25μmol/L AG490处NHela细胞24小时就开始表现出增殖抑制效应,72小时后表现出明显的抑制效应,细胞生存率持续下降(P＜0.05),有时间依赖性。4.阻断Stat3信号传导通路使宫颈癌细胞系细胞周期阻滞。50μmol/L AG490作用细胞48h后G0/G1期从(65.37±1.1 8)%上升至(74.67±3.13)%(P＜0.05),S期从(22.54±0.78)%下降至(17.45±1.45)%(P＜0.05),细胞基本阻滞于G0/G1期。同时,AG490对Hela细胞周期的阻滞作用有剂量依赖性。5.AG490促进宫颈癌细胞系凋亡。25umol/L AG490作用于Hela细胞24h后,流式细胞检测结果显示细胞凋亡率为(8.43±2.57)%。25μmol/L、50μmol/L、100μmol/LAG490处理Hela细胞48h后,凋亡率分别为(13.58±1.42)%,(23.44±1.55)%,(31.05±2.09)%,与对照组检测结果(2.99±0.75)%比较有统计学差异(P＜0.05),且各浓度组之间比较有统计学差异(F=131.15,P＜0.05),表明AG490促进Hela细胞凋亡并有浓度依赖效应。6.不同浓度AG490处理细胞后,Western blot检测发现各处理组JAK2及p-Stat3蛋白表达水平降低(P＜0.05),Stat3蛋白表达与对照组之间变化不大(P＞0.05)。7.不同浓度AG490作用于Hela细胞后Stat3信号通路下游靶基因产物CyclinD1及Survivin表达下调。经Pearson's相关性分析显示,在宫颈癌细胞中p-Stat3与CyclinD1及Survivin表达呈线性相关(r=0.901,P＜0.01;r=0.844,P＜0.01),提示CyclinD1及Survivin作为STAT3信号转导通路的重要下游基因产物,参与了Hela细胞的细胞周期、增殖及凋亡的调控。
结论:1.从蛋白水平证实宫颈癌中存在着组成性激活的Stat3信号通路。2.AG490可以特异地阻断Hela细胞中组成性激活的Stat3信号通路。3.AG490阻断Stat3转导通路后,宫颈癌细胞系Hela细胞的G0/G1期比例明显增高,S期细胞比率降低,细胞周期阻滞,细胞的增殖水平显著下降,该效应主要是通过调节Stat3信号通路下游靶基因产物CyclinD1来实现。4.AG490能够抑制宫颈癌细胞的增殖,促进细胞凋亡,主要是通过下调Stat3信号通路下游产物Survivin来实现。5.AG490可使JAK2,p-Stat3及下游靶基因产物CyclinD1、Survivin表达下调,同时p-Stat3与CyclinD1及Survivin表达呈正相关。6.Stat3信号转导通路通过调控下游靶基因产物CyclinD1、Survivin来促进人宫颈癌细胞系的细胞周期进行,加快细胞增殖,抑制细胞凋亡,参与宫颈癌的发生发展,通过阻断该通路来进行分子靶向治疗。7.p-Stat3蛋白可作为宫颈癌早期诊断、观察病情的一种生物学指标。
Objective: To study the expressions of Stat3, p-Stat3, CyclinD1 and Survivin in cervical cancer cell lines. The correlation between p-Stat3, CyclinD1 and Survivin were also observed. After treated by AG490 (a selective inhibitor of JAK2), we studied the relationship between the cervical cancer cell life cycle and the expressions of JAK2, Stat3, p-Stat3, CyclinD1 and Survivin protein. The potential mechanism of Stat3 signal transduction pathway in controlling the cancer cell transformation from G1 to S stage, proliferation and apoptosis was analysed to search for new biologic marker for diagnosis and therapy in human cervical cancer at early process. Finaly, the regulating mechanism of drug to occurre and develop cervical cancer by blocking Stat3 signal pathway was tried to explain.
Methods: 1.Hela cells were cultured in vitro. 2. Western-blot technique was used for detecting the protein expressions of Stat3, p-Stat3, and their downstream target gene product CyclinD1 and Survivin in human cervical cancer cell lines. 3. Hela cells were treated with different AG490 as experiment group, and the serum-free medium was used as control group. The blank control group did not plant cells at all. 4. Cell proliferation was detected by MTT assay. 5. Flow cytometry was applied to analyze the cell cycle and apoptosis. 6. The expressions of phosphorylation-JAK2 (JAK2), phosphorylation-Stat3 (p-Stat3), Stat3, CyclinD1 and Survivin were measured by Western blot after different AG490 treating. The correlation between p-Stat3, CyclinD1 and Survivin were also investigated.
Results: 1. Constitutively activated Stat3 signal existed in human cervical cancer cell lines. 2. Western Blotting showed that the vary tendency of CyclinD1 and Survivin expressions was similar to that of p-Stat3. 3. Proliferation of Hela cells decreased by concentration-depended manner after treatment with AG490. Detected at different doses after AG490 treating for 48h, the inhibition rate increased when AG490 concentration raised from 25 to 100μmol/L (P < 0.05). Three doses of AG490 treated expenriment groups have statistic meaning compared with control group(P < 0.01). Detected inhibition rate at different time after treatment with AG490 showed that some inhibition effects were found after 24h. The effect became obvious after treatment about 72h and cell survival rate decreased constantly (P < 0.05). 4. Stat3 signal transduction pathway contributes to the change of Hela cell from G1 phase to S phase. It was found that the cell proportion of G0/G1 phase increased from (65.37±1.18)% to (74.67±3.13)% (P < 0.05), and S phase decreased from (22.54±0.78)% to (17.45±1.45)% (P < 0.05). AG490 blocked Hela cell life cycle by concentration-dependent manner. 5. AG490 promoted the apoptosis of Hela cells. AG490 was used to treat Hela cells for 24h, and the percentage of apoptotic cells raised from (1.51±0.03)% to (8.43±2.57)%(P < 0.05). Detected apoptosis at 25μmol/L、50μmol/L、100μmol/L after AG490 treating 48h, the apoptosis rate was determined as (13.58±1.42)%, (23.44±1.55)%, (31.05±2.09)% respectively. Comparing the difference between control group and experiment groups have statistical significance (P < 0.05). Moreover, apoptosis rate differece of Hela cells with various concentration AG490 treating is significant (P < 0.05), which indicate AG490 induce Hela cells apoptosis with a concentration-dependent manner. 6. The expressions of JAK2 and p-Stat3 declined significantly (P < 0.05), but Stat3 had no obvious change after different concentration AG490 treating. 7. The expressions of CyclinD1 and Survivin decreased in Hela cells after AG490 treatment. Pearson's correlation analysis was used to analyse the correlation and variability of expressions of p-Stat3, CyclinD1 and Survivin in cervical cancer cell line. The expressions of p-Stat3 and CyclinD1 exhibit linear correlation (r=0.901, P < 0.01). Moreover, p-Stat3 and Survivin have the similar linear correlation (r=0.844, P < 0.01).
Conclusion: 1. The study of protein level confirmed that constitutive activation of Stat3 signal pathway exists in Hela cells. 2. AG490 can block Stat3 signal pathway selectively. 3. Blocking Stat3 pathway by AG490 in Hela cells, the cell cycle were changed, percentage of G0/G1 phase increased and S phase declined. Cell proliferation was also inhibited. The intrinsic mechanism is that AG490 downregulate the expression of CyclinD1. 4. AG490 inhibits Hela cells proliferation and promotes cell apoptosis through declining the expression of Survivin. 5. As targeted gene product, CyclinD1 and Survivin participate in the regulation of cell cycle, proliferation and apoptosis. 6. Stat3 signal pathway could be a novel target of cervical cancer therapy. 7. p-Stat3 can be a biologic marker for diagnosis and therapy in human cervical cancer at early process.
引文
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