HERG K~+通道参与急性白血病细胞迁移及黄连素的抑制作用
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摘要
第一部分HERG K~+离子通道在急性髓细胞白血病中的表达及其对细胞功能的调控
目的：herg(Human ether-a-go-go-related gene)基因编码HERG K~+离子通道常见于兴奋性细胞，但近来的研究显示herg也表达于各种肿瘤细胞，因此我们检测了急性髓细胞白血病中herg的表达，并进一步研究了herg对于白血病细胞的调控。
方法：Ficoll分离急性髓细胞白血病标本骨髓单个核细胞，Trizol提取白血病细胞系和骨髓单个核细胞RNA，rt-PCR检测herg基因的表达，CCK-8法测定HL-60细胞增殖活性，流式细胞术检测HL-60细胞周期变化，Annexin V/PI双标法检测HL-60细胞凋亡。
结果：herg在白血病细胞系HL-60，K562和Jurkat中均有表达，其中HL-60细胞表达最高。在我们检测的72％的白血病骨髓单个核细胞中表达但不表达于健康供体的骨髓单个核细胞，在CD34~+/CD38~-白血病干细胞中有微量表达。HERG K~+离子通道特异性抑制剂E-4031处理HL-60细胞后，使其增殖活性降低，细胞周期检测发现E-4031使G0/G1期细胞增多，但不影响HL-60细胞的凋亡。
结论：herg在白血病干/祖细胞水平就已经被激活，HERG K~+通道与白血病进展相关且能调控细胞增殖和周期。
第二部分黄连素抑制SDF-1诱导的急性髓细胞白血病细胞的迁移
目的：黄连素(bererine，Ber)又名小檗碱，有报道显示黄连素能抑制肿瘤细胞浸润。SDF-1是由骨髓基质细胞分泌的衍生因子，通过其受体CXCR4作用诱导白血病细胞迁移从而导致白血病浸润到其他器官，这里我们试图探求黄连素是否能够抑制SDF-1诱导的白血病细胞迁移及其基本机制。
方法：我们用了白血病细胞系HL-60，骨髓单个核细胞和白血病干细胞进行了实验。Ficoll分离白血病标本骨髓单个核细胞，8μm的transwell用于迁移实验来检测SDF-1诱导白血病细胞迁移及黄连素的抑制作用，应用流式细胞术来分析黄连素对白血病细胞CXCR4的表达和F-actin聚合能力的改变，用ELISA方法来检测骨髓基质细胞(BMMSCs)分泌的SDF-1的量，Akt和pAkt的表达用western blotting来检测。
结果：黄连素能对SDF-1诱导的急性髓性白血病细胞系HL-60，骨髓单个核细胞和干细胞的迁移有显著的抑制作用，且黄连素能够减少骨髓基质细胞分泌SDF-1的量但是并不影响SDF-1受体CXCR4的表达，黄连素能影响F-actin的聚合且能使pAkt表达量减少，SDF-1诱导能激活Akt信号通路，Akt抑制剂LY2904002能抑制SDF-1诱导的HL-60细胞迁移，且呈剂量依赖性。
结论：黄连素一方面能通过抑制F-actin聚合和减少Akt的磷酸化活化而抑制白血病细胞迁移，另一方面能减少骨髓微环境SDF-1的表达，因而从两个方面来抑制白血病细胞的迁移和浸润，因此黄连素可能是一种潜在有效的治疗的白血病药物。
第三部分HERG K~+离子通道在细胞迁移中的作用及SDF-1对其生理活性的影响
目的：基质细胞衍生因子(SDF-1)及其唯一的受体CXCR4调节骨髓中干/祖细胞的迁移和滞留是造血过程所必须的。前面的研究显示herg在白血病细胞中异常表达且黄连素能显著抑制SDF-1诱导的白血病细胞迁移，有研究显示黄连素是HERG K~+离子通道抑制剂。因此，我们试图探讨HERG K~+通道是否参与SDF-1诱导的细胞迁移过程。
方法：HEK293T细胞用于来表达外源性的HERG K~+通道蛋白。8μm的transwell用于迁移实验来检测转染和未转染细胞迁移情况，应用流式细胞术来分析F-actin聚合，HERG K~+通道电流用全细胞膜片钳的方法检测。
结果：我们成功的在HEK293T细胞中表达了HERG K~+离子通道。herg转染能使293T细胞迁移增加，但使细胞增殖减少。黄连素能抑制HERG K~+电流，且能显著的抑制herg-pEGFP转染的HEK293T细胞的迁移，SDF-1能使herg-pEGFP转染的HEK293T细胞HERG K~+尾电流增加。
结论：HERG K~+离子通道的活性与细胞迁移有一定相关性，且SDF-1使HERG K~+电流增加，黄连素可能通过抑制HERG K~+电流来抑制SDF-1诱导的细胞迁移。
PartⅠHERG K~+ channels expression and analysis of itsregulation in leukemic cells
Objective: The human ether-a-go-go-related (herg) gene encoding K~+ channels(HERG) belongs to an evolutionarily conserved multigene family of voltage activated K~+channels and their contribution to the repolarization of the cardiac action potential are wellunderstood. Recent studies revealed that HERG K~+ channels are preferentially expressed indifferent histogenesis of tumor cells. Here we tried to explore the expression of herg inleukemic cells and CD34~+/CD38~- LSCs and tried to explore its regulation of leukemic cellsactivities such as proliferation, cell cycle and apoptosis.
Method: Ficoll was used to isolate the bone marrow mononuclear cells, total RNAwas extracted and its purity and integrity was checked by running an aliquot on a 1.5%agarose gel and rt-PCR was used to evaluate the herg expression of different samples,CCK-8 kit was used to study cell proliferation. Flow cytometry was used to analyze HL-60cell cycle and apoptosis.
Result: herg was aberrantly expressed in leukemic cell lines, CD34~+/CD38~- LSCs andprimary leukemic cells but not expressed in normal bone marrow mononuclear cells. Inaddition, the expression of herg mRNA was not associated with the clinical and cytogeneticfeature of leukemia. Our results showed that HL-60 cell proliferation was dramaticallyinhibited by blocking HERG K~+ channels with E-4031, a HERG K~+ channels specificinhibitor. Moreover, E-4031could cause a marked reduction of the cell populations in Sphase along with significant increase in cell numbers in G1 phase but did not cause cellsapoptosis.
Conclusion: These data provided evidence for the oncogenic potential of HERG K~+channels and it may be a novel, potential marker of leukemia diagnosis in the future.
PartⅡBerberine inhibits SDF-1-induced AML cells and leukemicstem cells migration via regulation of SDF-1 level in bone marrowstromal cells
Objective: Berberine is an isoquinoline derivative alkaloid isolated from manymedical herbs. Emerging evidences indicate the functional role of berberine on thedevelopment of cancer, berberine plays a prominent role in the control of tumor cellproliferation and invasion, but there is no report about berberine functional role onleukemia at present. SDF-1 is a homeostatic chemokine that signals through CXCR4 whichis expressed by hematopoietic tumor cells. The SDF-1/CXCR4 axis is involved in themigration process of leukemic cells. In this study, we investigated the effects of berberineon the SDF-1-induced HL-60 cells, primary AML cells and leukemic stem cells .(LSCs)migration.
Method: Transwell migration chambers (8μm) were used to assess the role ofberberine on leukemic cell migration; Flow cytometry was used to analyze the role ofberberine on the CXCR4 expression and F-actin polymerlization; SDF-1 protein levelsecreted by bone marrow stromal cells (BMSCs) was evaluated by ELISA, western blottingwas used to detect the level of Akt and pAkt.
Result: Our data demonstrated that berberine could partly inhibit SDF-1-inducedAML cells as well as LSCs migration. Berberine could reduce SDF-1 protein level secretedby BMSCs in the microenvironment but not affect CXCR4 expression on HL-60 cellmembrane. Berberine could inhibit F-actin polymerization and decrease the expression ofpAkt, SDF-lcould activate the Akt signal pathway and Akt inhibitor, LY2904002, couldinhibit the SDF-1 induced HL-60 cells migration as dose-dependent.
Conclusion: Berberine could inhibit AML cells migration partly by reducing thesecreting of SDF-1 by BMSC and inhibiting HERG1 Kt channels of leukemic cells.Therefore, it is speculated that berberine might be a potentially effective agent forprevention of leukemia.
PartⅢHERG K~+ channels role in cells migration anda functional link between HERG K~+ channels and SDF-1
Objective: Stromal cell-derived factor-1 (SDF-1) and its unique receptor, CXCR4,regulate stem/progenitor cell migration and retention in the marrow and are required forhematopoiesis. Recent studies suggested that HERG K~+ channels were important regulatorsof non excitable cells migration and found in tumor cells. In this study, we investigatedwhether SDF-1-induced acute leukemic cell migration associated with HERG K~+ channels.
Method: Transient transfected HEK293T was used to express HERG K~+ channels,transwell was used to acess cell migration, flow cytometry was used to F-actinpolymerization, HERG1 K~+ currents were measured by the standard two microelectrodevoltage clamp techniques.
Result: Our data showed that berberine could specifically block HERG1 K~+ channelsand significantly blocked migration of HEK293T cells transfected with herg-pEGFP.Berberine could also decrease the F-actin polymerization in transient transfected HEK293T.SDF-1 increased HERG1 K~+ current expressed in HEK293T cells transfected withherg-pEGFP.
Conclusion: The HERG K~+ current increased by SDF-1 might contribute to themechanism of SDF-1 induced cell migration and berberine which could be a specificHERG K~+ inhibitor decreased the cells migration induced by SDF-1. The data showed thatHERG K~+ channels were essential for cells migration induced by SDF-1.
目的：herg(Human ether-a-go-go-related gene)基因编码HERG K~+离子通道常见于兴奋性细胞，但近来的研究显示herg也表达于各种肿瘤细胞，因此我们检测了急性髓细胞白血病中herg的表达，并进一步研究了herg对于白血病细胞的调控。
方法：Ficoll分离急性髓细胞白血病标本骨髓单个核细胞，Trizol提取白血病细胞系和骨髓单个核细胞RNA，rt-PCR检测herg基因的表达，CCK-8法测定HL-60细胞增殖活性，流式细胞术检测HL-60细胞周期变化，Annexin V/PI双标法检测HL-60细胞凋亡。
结果：herg在白血病细胞系HL-60，K562和Jurkat中均有表达，其中HL-60细胞表达最高。在我们检测的72％的白血病骨髓单个核细胞中表达但不表达于健康供体的骨髓单个核细胞，在CD34~+/CD38~-白血病干细胞中有微量表达。HERG K~+离子通道特异性抑制剂E-4031处理HL-60细胞后，使其增殖活性降低，细胞周期检测发现E-4031使G0/G1期细胞增多，但不影响HL-60细胞的凋亡。
结论：herg在白血病干/祖细胞水平就已经被激活，HERG K~+通道与白血病进展相关且能调控细胞增殖和周期。
第二部分黄连素抑制SDF-1诱导的急性髓细胞白血病细胞的迁移
目的：黄连素(bererine，Ber)又名小檗碱，有报道显示黄连素能抑制肿瘤细胞浸润。SDF-1是由骨髓基质细胞分泌的衍生因子，通过其受体CXCR4作用诱导白血病细胞迁移从而导致白血病浸润到其他器官，这里我们试图探求黄连素是否能够抑制SDF-1诱导的白血病细胞迁移及其基本机制。
方法：我们用了白血病细胞系HL-60，骨髓单个核细胞和白血病干细胞进行了实验。Ficoll分离白血病标本骨髓单个核细胞，8μm的transwell用于迁移实验来检测SDF-1诱导白血病细胞迁移及黄连素的抑制作用，应用流式细胞术来分析黄连素对白血病细胞CXCR4的表达和F-actin聚合能力的改变，用ELISA方法来检测骨髓基质细胞(BMMSCs)分泌的SDF-1的量，Akt和pAkt的表达用western blotting来检测。
结果：黄连素能对SDF-1诱导的急性髓性白血病细胞系HL-60，骨髓单个核细胞和干细胞的迁移有显著的抑制作用，且黄连素能够减少骨髓基质细胞分泌SDF-1的量但是并不影响SDF-1受体CXCR4的表达，黄连素能影响F-actin的聚合且能使pAkt表达量减少，SDF-1诱导能激活Akt信号通路，Akt抑制剂LY2904002能抑制SDF-1诱导的HL-60细胞迁移，且呈剂量依赖性。
结论：黄连素一方面能通过抑制F-actin聚合和减少Akt的磷酸化活化而抑制白血病细胞迁移，另一方面能减少骨髓微环境SDF-1的表达，因而从两个方面来抑制白血病细胞的迁移和浸润，因此黄连素可能是一种潜在有效的治疗的白血病药物。
第三部分HERG K~+离子通道在细胞迁移中的作用及SDF-1对其生理活性的影响
目的：基质细胞衍生因子(SDF-1)及其唯一的受体CXCR4调节骨髓中干/祖细胞的迁移和滞留是造血过程所必须的。前面的研究显示herg在白血病细胞中异常表达且黄连素能显著抑制SDF-1诱导的白血病细胞迁移，有研究显示黄连素是HERG K~+离子通道抑制剂。因此，我们试图探讨HERG K~+通道是否参与SDF-1诱导的细胞迁移过程。
方法：HEK293T细胞用于来表达外源性的HERG K~+通道蛋白。8μm的transwell用于迁移实验来检测转染和未转染细胞迁移情况，应用流式细胞术来分析F-actin聚合，HERG K~+通道电流用全细胞膜片钳的方法检测。
结果：我们成功的在HEK293T细胞中表达了HERG K~+离子通道。herg转染能使293T细胞迁移增加，但使细胞增殖减少。黄连素能抑制HERG K~+电流，且能显著的抑制herg-pEGFP转染的HEK293T细胞的迁移，SDF-1能使herg-pEGFP转染的HEK293T细胞HERG K~+尾电流增加。
结论：HERG K~+离子通道的活性与细胞迁移有一定相关性，且SDF-1使HERG K~+电流增加，黄连素可能通过抑制HERG K~+电流来抑制SDF-1诱导的细胞迁移。
PartⅠHERG K~+ channels expression and analysis of itsregulation in leukemic cells
Objective: The human ether-a-go-go-related (herg) gene encoding K~+ channels(HERG) belongs to an evolutionarily conserved multigene family of voltage activated K~+channels and their contribution to the repolarization of the cardiac action potential are wellunderstood. Recent studies revealed that HERG K~+ channels are preferentially expressed indifferent histogenesis of tumor cells. Here we tried to explore the expression of herg inleukemic cells and CD34~+/CD38~- LSCs and tried to explore its regulation of leukemic cellsactivities such as proliferation, cell cycle and apoptosis.
Method: Ficoll was used to isolate the bone marrow mononuclear cells, total RNAwas extracted and its purity and integrity was checked by running an aliquot on a 1.5%agarose gel and rt-PCR was used to evaluate the herg expression of different samples,CCK-8 kit was used to study cell proliferation. Flow cytometry was used to analyze HL-60cell cycle and apoptosis.
Result: herg was aberrantly expressed in leukemic cell lines, CD34~+/CD38~- LSCs andprimary leukemic cells but not expressed in normal bone marrow mononuclear cells. Inaddition, the expression of herg mRNA was not associated with the clinical and cytogeneticfeature of leukemia. Our results showed that HL-60 cell proliferation was dramaticallyinhibited by blocking HERG K~+ channels with E-4031, a HERG K~+ channels specificinhibitor. Moreover, E-4031could cause a marked reduction of the cell populations in Sphase along with significant increase in cell numbers in G1 phase but did not cause cellsapoptosis.
Conclusion: These data provided evidence for the oncogenic potential of HERG K~+channels and it may be a novel, potential marker of leukemia diagnosis in the future.
PartⅡBerberine inhibits SDF-1-induced AML cells and leukemicstem cells migration via regulation of SDF-1 level in bone marrowstromal cells
Objective: Berberine is an isoquinoline derivative alkaloid isolated from manymedical herbs. Emerging evidences indicate the functional role of berberine on thedevelopment of cancer, berberine plays a prominent role in the control of tumor cellproliferation and invasion, but there is no report about berberine functional role onleukemia at present. SDF-1 is a homeostatic chemokine that signals through CXCR4 whichis expressed by hematopoietic tumor cells. The SDF-1/CXCR4 axis is involved in themigration process of leukemic cells. In this study, we investigated the effects of berberineon the SDF-1-induced HL-60 cells, primary AML cells and leukemic stem cells .(LSCs)migration.
Method: Transwell migration chambers (8μm) were used to assess the role ofberberine on leukemic cell migration; Flow cytometry was used to analyze the role ofberberine on the CXCR4 expression and F-actin polymerlization; SDF-1 protein levelsecreted by bone marrow stromal cells (BMSCs) was evaluated by ELISA, western blottingwas used to detect the level of Akt and pAkt.
Result: Our data demonstrated that berberine could partly inhibit SDF-1-inducedAML cells as well as LSCs migration. Berberine could reduce SDF-1 protein level secretedby BMSCs in the microenvironment but not affect CXCR4 expression on HL-60 cellmembrane. Berberine could inhibit F-actin polymerization and decrease the expression ofpAkt, SDF-lcould activate the Akt signal pathway and Akt inhibitor, LY2904002, couldinhibit the SDF-1 induced HL-60 cells migration as dose-dependent.
Conclusion: Berberine could inhibit AML cells migration partly by reducing thesecreting of SDF-1 by BMSC and inhibiting HERG1 Kt channels of leukemic cells.Therefore, it is speculated that berberine might be a potentially effective agent forprevention of leukemia.
PartⅢHERG K~+ channels role in cells migration anda functional link between HERG K~+ channels and SDF-1
Objective: Stromal cell-derived factor-1 (SDF-1) and its unique receptor, CXCR4,regulate stem/progenitor cell migration and retention in the marrow and are required forhematopoiesis. Recent studies suggested that HERG K~+ channels were important regulatorsof non excitable cells migration and found in tumor cells. In this study, we investigatedwhether SDF-1-induced acute leukemic cell migration associated with HERG K~+ channels.
Method: Transient transfected HEK293T was used to express HERG K~+ channels,transwell was used to acess cell migration, flow cytometry was used to F-actinpolymerization, HERG1 K~+ currents were measured by the standard two microelectrodevoltage clamp techniques.
Result: Our data showed that berberine could specifically block HERG1 K~+ channelsand significantly blocked migration of HEK293T cells transfected with herg-pEGFP.Berberine could also decrease the F-actin polymerization in transient transfected HEK293T.SDF-1 increased HERG1 K~+ current expressed in HEK293T cells transfected withherg-pEGFP.
Conclusion: The HERG K~+ current increased by SDF-1 might contribute to themechanism of SDF-1 induced cell migration and berberine which could be a specificHERG K~+ inhibitor decreased the cells migration induced by SDF-1. The data showed thatHERG K~+ channels were essential for cells migration induced by SDF-1.
引文
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