5-FU和MG132选择性调控NKG2D配体表达及其机制初步研究
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摘要
NK细胞是天然免疫的主要承担者,在肿瘤免疫、抗病毒感染及清除非己细胞中发挥重要作用【1-4】。与T细胞不同的是,NK细胞的细胞毒作用不受肿瘤细胞的MHC-Ⅰ类分子的限制,其细胞活性的发挥是其表达的各种受体分子与相应配体相互作用的结果。
NKG2D (NK group 2, member D)为NK细胞表面活化性受体,属C型凝集素超家族成员。NKG2D可以广泛地表达于多种免疫细胞【5,6】,如所有NK细胞表面以及部分NKT细胞、部分T细胞【7】。NKG2D的配体为MHC-I类相关分子(MHC class I-related molecules, MICs),包括MICA、MICB和ULBP1-5(病毒UL16结合蛋白)等【8】。MICA/B和ULBP1~3可被金属蛋白酶作用而从细胞表面脱落【9】。MICs为“诱导型”细胞表面抗原【10,11】,近年的研究【12】发现许多因素,如细胞应激、热休克、感染、DNA损伤和转化等均可上调它们的表达,病毒miRNA、基质金属蛋白酶等可影响NKG2D配体的表达【13-17】。
研究表明,由于肿瘤细胞的MHC-I类分子丢失或变异,使得特异性MHC限制性的细胞毒T细胞不能发挥作用。在这种情况下,识别非MHC-I类分子的NKG2D在介导NK细胞识别和溶解肿瘤细胞的免疫反应中发挥关键的作用【18,19】。NKG2D通过与靶细胞表面诱导产生的相应配体结合,然后结合转接蛋白向NK细胞传递活化信号,使NK细胞获得攻击靶细胞的能力【20】。另外还为CD8 + T细胞提供必要的协同刺激信号,因此在很大程度上NKG2D途径的活化决定了机体的抗肿瘤细胞免疫水平。
文献报道DNA损伤反应可以通过诱导NKG2D配体的上调来增加肿瘤细胞对NK细胞的敏感性【21-24】,因此激活DNA损伤反应的药物/治疗方法(如放疗、化疗)和NK细胞治疗联合应用,有可能减少药物的副作用,提高肿瘤细胞对NK细胞杀伤的敏感性,提高抗肿瘤效果。
目前,化疗联合基于NK细胞的免疫治疗在临床上应用广泛,但化疗对NK细胞抗肿瘤活性的调节机制,尤其是对NKG2D介导的杀伤机制是如何调节的还不甚清楚。为什么同一个NKG2D受体在细胞上存在多种不同的配体?它们的作用有何差异?表达调控上有何不同?不同的化疗药物所造成的损伤不同,其调控NKG2D配体表达的通路差异是什么?虽然NKG2D配体编码区有一定保守性,但其5’非翻译区同源性很低,提示不同刺激或病变对不同的NKG2D配体的表达调控可能是特异的。
因此,本研究以肺腺癌A549细胞系为模型,研究不同作用机制的抗代谢抗肿瘤药5-FU和蛋白酶体抑制剂MG132对A549细胞的NKG2D配体表达及对NK细胞杀伤敏感性的影响,并探讨其可能的调控机制。
目的:研究5-FU和MG132对A549细胞NKG2D配体表达的调控及其机制。
方法:采用PCR方法,以A549细胞的全基因组为模板,扩增人NKG2D配体MICA/B的启动子及其5个截短体基因,并亚克隆入pGL3-Basic报告基因载体,转染A549细胞后运用双荧光报告基因系统进行启动子活性分析。用MTT法检测了不同浓度5-FU和MG132对A549细胞的抑制率;测定了300μM 5-FU、10μM MG132处理对MICA/B启动子活性的影响。采用荧光定量PCR和流式细胞术检测5-FU和MG132对NKG2D配体在mRNA、细胞表面蛋白水平上的表达变化;用彗星法观察5-FU和MG132处理A549后DNA的损伤情况;Western blot检测DNA损伤反应通路中信号分子Chk1、Chk2蛋白磷酸化;并观察了DNA损伤反应通路分子抑制剂对5-FU和MG132诱导NKG2D配体表达作用的影响。
结果:克隆了人MICA、MICB的启动子及其五个截短体基因并测定了启动子基础活性。5-FU可分别上调MICA/B启动子相对活性1.48和1.87倍, MG132可上调MICB启动子相对活性1.77倍。5-FU可提高MICB和ULBP2在mRNA水平的表达,分别是对照的1.76和3.28倍,而在细胞表面蛋白水平MICB蛋白表达水平没变化,ULBP2表达提高了16.05%;MG132可提高MICB、ULBP1、ULBP3在mRNA水平的表达,分别是对照的10.62、11.09和7.25倍,而细胞表面蛋白只有MICB、ULBP1表达分别提高了68.18%、23.65%。NK杀伤实验发现5-FU和MG132可提高NK细胞对A549细胞的杀伤率,NK对A549的杀伤作用可部分被NKG2D抗体、ULBP2抗体、MICB和ULBP1抗体抑制。5-FU和MG132处理可使A549细胞DNA发生损伤,彗星法(碱性裂解法)可观察到明显的拖尾现象,而且5-FU和MG132可分别使Chk1、Chk2发生磷酸化。使用ATM激酶抑制剂KU55933、Chk1抑制剂SB218078和PI3激酶抑制剂Wortmannin均可抑制5-FU和MG132引起的细胞表面ULBP2和MICB的表达上调。
结论:以上结果表明5-FU和MG132分别选择性上调了A549细胞表面ULBP2和MICB的表达,并增强了A549细胞对NKG2D及其相应配体介导的NK杀伤敏感性。5-FU对ULBP2表达的调节可能与DNA损伤反应通路中Chk1的磷酸化水平上升有关,MG132对MICB表达的调节可能与Chk2的磷酸化水平增加有关。
NK cells are major effector cells of innate immune system, playing an important role in tumor immunity, antiviral infection and removal of‘non-self’cells [1-4]. The difference between T cells and NK cells is that toxic effect of the latter is not restrained by MHC- I molecules of tumor cells, and the cell activity is the result of the interaction of various receptor molecules with corresponding ligands.
NKG2D (NK group 2, member D) is receptor of activation and belongs to the type of c-lectin superfamily. NKG2D is widely expressed on many immune cells [5,6], such as all NK cell surface and some NKT cells, part of the T cells[7]. NKG2D ligands are MHC-I related molecules (MHC class I-related molecules MICs), including MICA, MICB, and ULBP1-5 [8] (Human cytomegalo virus UL16 protein binding proteins 1-5). MICs are induced cell surface antigen [10,11]. In recent years it has beeen found in studies that many factors, such as cell stress, heat shock, infection, DNA damage and transformation can up-regulate their expression [13-17].
Research shows that due to the lost or variation of MHC- I molecules on tumor cells, the specific MHC restrictive cytotoxic T cells can not play a role. In this case, the engagement of NKG2D to non MHC-I molecules (MICs) and subsequent dissolution of tumor cells in the immune response plays an important role [18,19]. Following the interaction of NKG2D and corresponding ligands induced on surface of target cells, NKG2D binds to adaptor protein and transmits activated signal to NK cells. In this way NK cells obtain the ability to attack the target cells [20]. In addition, CD8 + T-cells are provided with the necessary synergy stimulating signals, thus the activation of NKG2D pathway largely determines the intensity of cells immunity against cancer.
At present, NK cells based immuno-therapy combined with chemotherapy is clinically widely applied, but it is still unclear that how chemotherapy regulates the antitumor activity of NK cells, especially how NKG2D-mediated killing mechanism works. Why there are so many different ligands of the same NKG2D receptor exist on the cells? What are the different roles between them? What are the differences between their expression regulation? Different chemotherapy drugs cause different damages, then what is the difference of the regulation of NKG2D ligands expression between the different pathways? Although NKG2D ligands’coding regions are conservative, the homology of their 5 ' non-translation region is very low, which hints that the expression regulation of different NKG2D ligands may be specific by different stimuli or lesions.
Therefore, we use lung adenocarcinoma cell line A549 as the cell model to investigate the regulation effect of chemotherapeutic drug 5-FU and proteinase inhibitor MG132 on the expression of NKG2D ligands and the susceptibility of A549 cells to NK lysis. We also studied the possible regulatory mechanisms involed, focusing on the role of DNA damage response pathway. Objective: The research is to study the regulation effect of 5-FU and MG132 on the expression of NKG2D ligands on A549 cell lines and the mechanisms involved.
Methods: Genome DNA of A549 cells was isolated and the full-length and five truncated MICA/B promoter were amplified using polymerase chain reaction (PCR) method. The promoter genes were then cloned into the pGL3-Basic reporter vector and transfected into A549 cell. The promoter activity was analysed with Dual-Luciferase Reporter Assay System. The inhibition rates of A549 cells by different concentrations of 5-FU and MG132 were determined by MTT assay. A549 cells were treated with 300μM 5-FU and 10μM MG132 and the changes of MICA/B promoter activity, the mRNA expression of NKG2D ligands as well as the cell-surface expression levels of NKG2D ligands were measured by Dual-Luciferase Reporter Assay, fluorescence quantitative polymerase chain reaction (PCR) and Flow cytometry respectively. In order to investigate whether DNA damage was occurred after the treatment with 5-FU and MG132, We also performed comet assay to observe the DNA alteration. As for the mechanism research, the phosphorylation of Chk1 and Chk2, the molecules involved in the DNA damage response pathway, were tested by Western blot. In order to study whether blocking of ATM and Chk1 could interfere with the induction of NKG2D ligands, specific inhibitors were used to treat A549 cells and the expression of NKG2D ligands in present or absent of 5-FU and MG132 were investigated.
Results: We cloned MICA, MICB promoter and their five truncated genes. The activities of MICA/B promoter were 1.48 and 1.87 fold up-regulated respectively treated by 5-FU. The activity of MICB promoter was 1.77 fold up-regulated treated by MG132. After the treatment with 5-FU, the mRNA expression of MICB and ULBP2 were up-regulated 1.76 and 3.28 fold respectively, and the surface ULBP2 was increased by 16.05%, whereas the surface expressions of MICA/B did not change. After 8 hours’treatment with MG132, the mRNA expression of MICB, ULBP1 and ULBP3 were up-regulated 10.62, 11.09 and 7.25 fold respectively, and the surface MICB and ULBP1 were increased by 68.18% and 23.65%. 5-FU or MG132 treatment improved the cytotoxicity of NK cells and the A549 cell lysis were partly blocked by NKG2D antibody, ULBP2 antibody and MICB, ULBP1 antibody. KU55933(ATM Kinase Inhibitor), SB218078(Chk1 Inhibitor)and Wortmannin(the PI3 Kinase Inhibitor)could inhibit the surface expression of ULBP2 and MICB, ULBP1 induced by 5-FU and MG132. We observed a notable trailing phenomenon in A549 cells after treatment with 5-FU or MG132. Phosphorylation of Chk1, an event associated with DNA damage, was found after treatment of 5-FU. Phosphorylation of Chk2, an event associated with DNA damage, was found after treatment of MG132.
Conclusion: The results indicate that 5-FU and MG132 selectively up-regulate surface expression of ULBP2 and MICB on A549 cells, and increase the NKG2D mediated cytotoxicity of NK cells. The regulation effect of 5-FU and MG132 is related to the activation of Chk1 and Chk2, an event associated with DNA damage.
NKG2D (NK group 2, member D)为NK细胞表面活化性受体,属C型凝集素超家族成员。NKG2D可以广泛地表达于多种免疫细胞【5,6】,如所有NK细胞表面以及部分NKT细胞、部分T细胞【7】。NKG2D的配体为MHC-I类相关分子(MHC class I-related molecules, MICs),包括MICA、MICB和ULBP1-5(病毒UL16结合蛋白)等【8】。MICA/B和ULBP1~3可被金属蛋白酶作用而从细胞表面脱落【9】。MICs为“诱导型”细胞表面抗原【10,11】,近年的研究【12】发现许多因素,如细胞应激、热休克、感染、DNA损伤和转化等均可上调它们的表达,病毒miRNA、基质金属蛋白酶等可影响NKG2D配体的表达【13-17】。
研究表明,由于肿瘤细胞的MHC-I类分子丢失或变异,使得特异性MHC限制性的细胞毒T细胞不能发挥作用。在这种情况下,识别非MHC-I类分子的NKG2D在介导NK细胞识别和溶解肿瘤细胞的免疫反应中发挥关键的作用【18,19】。NKG2D通过与靶细胞表面诱导产生的相应配体结合,然后结合转接蛋白向NK细胞传递活化信号,使NK细胞获得攻击靶细胞的能力【20】。另外还为CD8 + T细胞提供必要的协同刺激信号,因此在很大程度上NKG2D途径的活化决定了机体的抗肿瘤细胞免疫水平。
文献报道DNA损伤反应可以通过诱导NKG2D配体的上调来增加肿瘤细胞对NK细胞的敏感性【21-24】,因此激活DNA损伤反应的药物/治疗方法(如放疗、化疗)和NK细胞治疗联合应用,有可能减少药物的副作用,提高肿瘤细胞对NK细胞杀伤的敏感性,提高抗肿瘤效果。
目前,化疗联合基于NK细胞的免疫治疗在临床上应用广泛,但化疗对NK细胞抗肿瘤活性的调节机制,尤其是对NKG2D介导的杀伤机制是如何调节的还不甚清楚。为什么同一个NKG2D受体在细胞上存在多种不同的配体?它们的作用有何差异?表达调控上有何不同?不同的化疗药物所造成的损伤不同,其调控NKG2D配体表达的通路差异是什么?虽然NKG2D配体编码区有一定保守性,但其5’非翻译区同源性很低,提示不同刺激或病变对不同的NKG2D配体的表达调控可能是特异的。
因此,本研究以肺腺癌A549细胞系为模型,研究不同作用机制的抗代谢抗肿瘤药5-FU和蛋白酶体抑制剂MG132对A549细胞的NKG2D配体表达及对NK细胞杀伤敏感性的影响,并探讨其可能的调控机制。
目的:研究5-FU和MG132对A549细胞NKG2D配体表达的调控及其机制。
方法:采用PCR方法,以A549细胞的全基因组为模板,扩增人NKG2D配体MICA/B的启动子及其5个截短体基因,并亚克隆入pGL3-Basic报告基因载体,转染A549细胞后运用双荧光报告基因系统进行启动子活性分析。用MTT法检测了不同浓度5-FU和MG132对A549细胞的抑制率;测定了300μM 5-FU、10μM MG132处理对MICA/B启动子活性的影响。采用荧光定量PCR和流式细胞术检测5-FU和MG132对NKG2D配体在mRNA、细胞表面蛋白水平上的表达变化;用彗星法观察5-FU和MG132处理A549后DNA的损伤情况;Western blot检测DNA损伤反应通路中信号分子Chk1、Chk2蛋白磷酸化;并观察了DNA损伤反应通路分子抑制剂对5-FU和MG132诱导NKG2D配体表达作用的影响。
结果:克隆了人MICA、MICB的启动子及其五个截短体基因并测定了启动子基础活性。5-FU可分别上调MICA/B启动子相对活性1.48和1.87倍, MG132可上调MICB启动子相对活性1.77倍。5-FU可提高MICB和ULBP2在mRNA水平的表达,分别是对照的1.76和3.28倍,而在细胞表面蛋白水平MICB蛋白表达水平没变化,ULBP2表达提高了16.05%;MG132可提高MICB、ULBP1、ULBP3在mRNA水平的表达,分别是对照的10.62、11.09和7.25倍,而细胞表面蛋白只有MICB、ULBP1表达分别提高了68.18%、23.65%。NK杀伤实验发现5-FU和MG132可提高NK细胞对A549细胞的杀伤率,NK对A549的杀伤作用可部分被NKG2D抗体、ULBP2抗体、MICB和ULBP1抗体抑制。5-FU和MG132处理可使A549细胞DNA发生损伤,彗星法(碱性裂解法)可观察到明显的拖尾现象,而且5-FU和MG132可分别使Chk1、Chk2发生磷酸化。使用ATM激酶抑制剂KU55933、Chk1抑制剂SB218078和PI3激酶抑制剂Wortmannin均可抑制5-FU和MG132引起的细胞表面ULBP2和MICB的表达上调。
结论:以上结果表明5-FU和MG132分别选择性上调了A549细胞表面ULBP2和MICB的表达,并增强了A549细胞对NKG2D及其相应配体介导的NK杀伤敏感性。5-FU对ULBP2表达的调节可能与DNA损伤反应通路中Chk1的磷酸化水平上升有关,MG132对MICB表达的调节可能与Chk2的磷酸化水平增加有关。
NK cells are major effector cells of innate immune system, playing an important role in tumor immunity, antiviral infection and removal of‘non-self’cells [1-4]. The difference between T cells and NK cells is that toxic effect of the latter is not restrained by MHC- I molecules of tumor cells, and the cell activity is the result of the interaction of various receptor molecules with corresponding ligands.
NKG2D (NK group 2, member D) is receptor of activation and belongs to the type of c-lectin superfamily. NKG2D is widely expressed on many immune cells [5,6], such as all NK cell surface and some NKT cells, part of the T cells[7]. NKG2D ligands are MHC-I related molecules (MHC class I-related molecules MICs), including MICA, MICB, and ULBP1-5 [8] (Human cytomegalo virus UL16 protein binding proteins 1-5). MICs are induced cell surface antigen [10,11]. In recent years it has beeen found in studies that many factors, such as cell stress, heat shock, infection, DNA damage and transformation can up-regulate their expression [13-17].
Research shows that due to the lost or variation of MHC- I molecules on tumor cells, the specific MHC restrictive cytotoxic T cells can not play a role. In this case, the engagement of NKG2D to non MHC-I molecules (MICs) and subsequent dissolution of tumor cells in the immune response plays an important role [18,19]. Following the interaction of NKG2D and corresponding ligands induced on surface of target cells, NKG2D binds to adaptor protein and transmits activated signal to NK cells. In this way NK cells obtain the ability to attack the target cells [20]. In addition, CD8 + T-cells are provided with the necessary synergy stimulating signals, thus the activation of NKG2D pathway largely determines the intensity of cells immunity against cancer.
At present, NK cells based immuno-therapy combined with chemotherapy is clinically widely applied, but it is still unclear that how chemotherapy regulates the antitumor activity of NK cells, especially how NKG2D-mediated killing mechanism works. Why there are so many different ligands of the same NKG2D receptor exist on the cells? What are the different roles between them? What are the differences between their expression regulation? Different chemotherapy drugs cause different damages, then what is the difference of the regulation of NKG2D ligands expression between the different pathways? Although NKG2D ligands’coding regions are conservative, the homology of their 5 ' non-translation region is very low, which hints that the expression regulation of different NKG2D ligands may be specific by different stimuli or lesions.
Therefore, we use lung adenocarcinoma cell line A549 as the cell model to investigate the regulation effect of chemotherapeutic drug 5-FU and proteinase inhibitor MG132 on the expression of NKG2D ligands and the susceptibility of A549 cells to NK lysis. We also studied the possible regulatory mechanisms involed, focusing on the role of DNA damage response pathway. Objective: The research is to study the regulation effect of 5-FU and MG132 on the expression of NKG2D ligands on A549 cell lines and the mechanisms involved.
Methods: Genome DNA of A549 cells was isolated and the full-length and five truncated MICA/B promoter were amplified using polymerase chain reaction (PCR) method. The promoter genes were then cloned into the pGL3-Basic reporter vector and transfected into A549 cell. The promoter activity was analysed with Dual-Luciferase Reporter Assay System. The inhibition rates of A549 cells by different concentrations of 5-FU and MG132 were determined by MTT assay. A549 cells were treated with 300μM 5-FU and 10μM MG132 and the changes of MICA/B promoter activity, the mRNA expression of NKG2D ligands as well as the cell-surface expression levels of NKG2D ligands were measured by Dual-Luciferase Reporter Assay, fluorescence quantitative polymerase chain reaction (PCR) and Flow cytometry respectively. In order to investigate whether DNA damage was occurred after the treatment with 5-FU and MG132, We also performed comet assay to observe the DNA alteration. As for the mechanism research, the phosphorylation of Chk1 and Chk2, the molecules involved in the DNA damage response pathway, were tested by Western blot. In order to study whether blocking of ATM and Chk1 could interfere with the induction of NKG2D ligands, specific inhibitors were used to treat A549 cells and the expression of NKG2D ligands in present or absent of 5-FU and MG132 were investigated.
Results: We cloned MICA, MICB promoter and their five truncated genes. The activities of MICA/B promoter were 1.48 and 1.87 fold up-regulated respectively treated by 5-FU. The activity of MICB promoter was 1.77 fold up-regulated treated by MG132. After the treatment with 5-FU, the mRNA expression of MICB and ULBP2 were up-regulated 1.76 and 3.28 fold respectively, and the surface ULBP2 was increased by 16.05%, whereas the surface expressions of MICA/B did not change. After 8 hours’treatment with MG132, the mRNA expression of MICB, ULBP1 and ULBP3 were up-regulated 10.62, 11.09 and 7.25 fold respectively, and the surface MICB and ULBP1 were increased by 68.18% and 23.65%. 5-FU or MG132 treatment improved the cytotoxicity of NK cells and the A549 cell lysis were partly blocked by NKG2D antibody, ULBP2 antibody and MICB, ULBP1 antibody. KU55933(ATM Kinase Inhibitor), SB218078(Chk1 Inhibitor)and Wortmannin(the PI3 Kinase Inhibitor)could inhibit the surface expression of ULBP2 and MICB, ULBP1 induced by 5-FU and MG132. We observed a notable trailing phenomenon in A549 cells after treatment with 5-FU or MG132. Phosphorylation of Chk1, an event associated with DNA damage, was found after treatment of 5-FU. Phosphorylation of Chk2, an event associated with DNA damage, was found after treatment of MG132.
Conclusion: The results indicate that 5-FU and MG132 selectively up-regulate surface expression of ULBP2 and MICB on A549 cells, and increase the NKG2D mediated cytotoxicity of NK cells. The regulation effect of 5-FU and MG132 is related to the activation of Chk1 and Chk2, an event associated with DNA damage.
引文
【1】Anick Chalifour, Le′onardo Scarpellino, et al. A Role for cis Interaction between the Inhibitory Ly49A Receptor and MHC Class I for Natural Killer Cell Education. Immunity, 2008,30:337-347.
【2】Stephan Gasser. Activation and self-tolerance of natural killer cells.Immunological Reviews, 2006, 214:130-142.
【3】Ainhoa Arina1, Oihana Murillo1, et al. The combined actions of NK and T lymphocytes are ecessary to reject an EGFP+ mesenchymal tumor through mechanisms dependent on NKG2D and IFNγ. Cancer, 2007,121:1282-1295.
【4】Hans-Gustaf Ljunggren and Karl-Johan Malmberg, et al. Prospects for the use of NK cells in immunotherapy of human cancer. Immunology, 2007,7:329-339.
【5】Michael T. Borchers,Nathaniel L. Harris, et al. NKG2D ligands are expressed on stressed human airway epithelial cells. Physiol Lung Cell Mol Physiol, 2006,291:L222-L231.
【6】Steven J. Burgess, Kerima Maasho, et al. The NKG2D receptor: immunobiology and clinical Implications. Immunol Res, 2008, 40:18-34.
【7】Coudert JD, Held W,et al. The role of the NKG2D receptor for tumor immunity. Seminars in cancer biology, 2006;16:333-343.
【8】Robert A. Eagle, James A. Traherne, et al. Regulation of NKG2D Ligand Gene Expression, Human Immunology. 2006,67: 159-169.
【9】Gu¨nter Eisele, Jo¨rg Wischhusen, et al. TGF-βand metalloproteinases differentially suppress NKG2D ligand surface expression on malignant glioma cells. Brain ,2006, 129: 2416-2425.
【10】Noam Stern-Ginossar, Naama Elefant, et al. Host Immune System Gene Targeting by a Viral miRNA. Science, 2007,317:376-380.
【11】Stefan Bauer, Veronika Groh, et al. Activation of NK Cells and T Cells by NKG2D, a Receptor for Stress-Inducible MICA. Science, 1999, 285: 727-729.
【12】Cinzia Fionda,Alessandra Soriani, et al. Heat Shock Protein-90 Inhibitors Increase MHC Class I-Related Chain A and B Ligand Expression on Multiple Myeloma Cells and Their Ability to Trigger NK Cell Degranulation. The Journal of Immunology, 2009, 183: 4385-4394.
【13】Muzammel Haque, Keiji Ueda, Kazushi Nakano, et al. Major histocompatibility complex class I molecules are down-regulated at the cell surface by the K5 protein encoded by Kaposi’s sarcoma-associated herpesvirus/human herpesvirus-8. Journal of General Virology, 2001, 82:1175-1180.
【14】Manuel A. Friese,Jo¨rg Wischhusen, et al. RNA Interference Targeting Transforming Growth Factor-βEnhances NKG2D Mediated Antiglioma Immune Response, Inhibits Glioma Cell Migration and Invasiveness, and Abrogates Tumorigenicity In vivo. Cancer Research, 2004,64: 7596-7603.
【15】Daphna Nachmani, Noam Stern-Ginossar, et al. Diverse Herpesvirus MicroRNAs Target the Stress-Induced Immune Ligand MICB to Escape Recognition by Natural Killer Cells. Cell Host & Microbe, 2009, 5:376-385.
【16】Noam Stern-Ginossar,Naama Elefant, Albert Zimmermann, et al. Host Immune System Gene Targeting by a Viral miRNA. Science, 2007,317:376-380.
【17】Noam Stern-Ginossar, Chamutal Gur, et al. Human microRNAs regulate stress-induced immune responses mediated by the receptor NKG2D. Nature Immunology, 2008,9:1065-1073.
【18】Zamai L, Ponti C, Mirandola P, et al. NK cells and cancer. Immunol, 2007,178:4011-6.
【19】Smyth MJ, Swann J, Cretney E, et al. NKG2D function protects the host from tumor initiation. The journal of Experimental medicine, 2005,202:583-588.
【20】Jun Wu, Yaoli Song, Alexander B. H. Bakker, et al. An Activating Immunoreceptor Complex Formed by NKG2D and DAP10. Science, 1999, 285:730-732.
【21】Stephan Gasser, Sandra Orsulic, et al. The DNA damage pathway regulates innate immune system ligands for the NKG2D receptor. Nature, 2005,436: 11860-1190.
【22】Stephan Gasser and David H. Raulet. The DNA Damage Response Arouses the Immune System. Cancer Res, 2006, 66(8):3959-3962.
【23】Stephan Gasser, et al. DNA damage response and development of targeted cancer treatments. Annals of Medicine, 2007,39: 457-464.
【24】Stephan Gasser, David Raulet. The DNA damage response, immunity and cancer. Seminars in Cancer Biology, 2006,16: 344-347.
【25】Bartkova J, HorejsíZ, Koed K., et al. DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature, 2005,434:864-70.
【26】Bartek J, Lukas J, Bartkova J. DNA damage response as an anti-cancer barrier: damage threshold and the concept of 'conditional haploinsufficiency'. Cell Cycle, 2007,6(19):2344-7.
【27】Chauhan D,Hideshima T,Anderson KC. Proteasome inhibition in multiple myeloma:therapeutic implication. Annu Rev Pharmacol Toxicol, 2005,45:465-476.
【28】Gopalakrishnan M. Venkataraman, Dominic Suciu, et al. Promoter Region Architecture and Transcriptional Regulation of the Genes for the MHC Class I-Related Chain A and B Ligands of NKG2D. The Journal of Immunology, 2007, 178: 961-969.
【29】丁芳,吕茂民.猪内源性反转录病毒5′非编码区启动子活性的分析.中国农业科学2007,40(2):379-384.
【30】康鲁东,吴伟芳.人前列腺特异性膜抗原基因启动子/增强子表达载体的构建及组织特异性鉴定.中国病理生理杂志,2007,23 (1) : 120 -123.
【31】卜友泉,宋方洲.人NFBD1启动子的鉴定与初步分析.中国生物化学与分子生物学报, 2007,23 (8) :631-637.
【32】张健,陈苏宁.人NDRG2启动子的克隆与活性鉴定.生物技术通讯,2007,18:009-011.
【33】单佑安,刘庆等. MD22基因启动子区- 1064、- 1625 SNP对启动子活性的影响.第三军医大学学报,2007,29,3:185-187.
【34】李新玲,杨传平. rd29A启动子的克隆及提高烟草抗逆性的研究.分子植物育种,2007,5 (1 ):37-42.
【35】张素萍,徐乃玉,童建.顺铂作用HeLa细胞的蛋白质组学研究.中华肿瘤防治杂志,2008,15(3):174-177.
【36】刘华英,罗晓敏,李夏雨等.过表达E2F6基因抑制BRD7基因启动子活性. Chinese Journal of Biochemistry and Molecular Biology, 2006,22:886-893.
【37】Xue Li-xiang,Weng Mo,Zhang Zong-yu et al. Optimization of reporter gene assay:several factors influencing detection of promoter activity. Chin Med J,2007,120(11):965-969.
【38】朱玉萍,何超,朱洪波等.结肠癌细胞获得性5氟尿嘧啶耐药的机制研究. Chinese Journal of Pathophysiology,2007,23(10):2007-2011.
【39】Robert A. Eagle, James A. Traherne, et al. .Regulation of NKG2D Ligand Gene Expression.Human Immunology.2006,67:159-169.
【40】Mair Thomas, Jessica M. Boname, et al. Down Regulation of NKG2D and NKp80 ligands by Kaposi’s arcoma-associated herpesvirus K5 protects against NK cell cytotoxicity. PNAS, 2008,105:1656-1661.
【41】Alejandro Lo′pez-Soto, et al. Transcriptional Regulation of ULBP1, a Human Ligand of the NKG2D Receptor. The Journal of Biological Chemistry, 2006,281:30419-30430.
【42】Cai Zhang, Yiping Wang, Zhixia Zhou, et al. Sodium butyrate upregulates expression of NKG2D ligand MICA/B in HeLa and HepG2 cell lines and increases their susceptibility to NK lysis. Cancer Immunol Immunother, 2009,58:1275-1285.
【43】易彤波,杨连粤等. Caspase-8在5氟尿嘧啶诱导肝癌细胞凋亡中的作用.中国普通外科杂志,2002,17:171-172.
【44】James E. Butler, Mikel B. Moore,Steven R. Presnell, et al.Proteasome Regulation of ULBP1 Transcription. The Journal of Immunology, 2009,182: 6600 -6609.
【45】J Bartek, J Bartkova and J Lukas, et al. DNA damage signalling guards against activated oncogenes and tumour Progression. Oncogene, 2007,26:7773-7779.
【46】Adelheid Cerwenka, et al. New twist on the regulation of NKG2D lidand expression. Exp. Med, 2009,206:265-268.
【47】Timothy J. Nice , Laurent Coscoy, et al. Posttranslational regulation of the NKG2D ligand Mult1 in response to cell stress. The Journal of Experimental Medicine, 2009,206:287-298.
【48】Yizhou Zou, Effect of Human Cytomegalovirus on Expression of MHC Class I-Related Chains A. The Journal of Immunology, 2005,174:3098-3104.
【49】James E. Butler, Mikel B. Moore, Proteasome Regulation of ULBP1 Transcription. The Journal of Immunology, 2009, 182: 6600 -6609.
【50】Luciana L. Molinero, Mercedes B. Fuertes, et al. NF-κB Regulates Expression of the MHC Class I-Related Chain A Gene in Activated T Lymphocytes. The Journal of Immunology, 2004, 173: 5583-5590.
【51】张惠兰,张珍祥,徐永健. NF-κB圈套寡核苷酸促进肺癌细胞.A549凋亡的作用中国病理生理杂志.2004,20 (12) :2294-2298.
【52】廖品琥,黄冰等.白细胞介素-1β激活核转录因子-κB介导A549细胞分泌白细胞介素-8的研究.临床麻醉学杂志, 2007,23:43-45.
【53】邢丽华,樊再雯,刘剑波.核因子-κB抑制剂联合顺铂对A549细胞株的影响.中国呼吸与危重监护杂志, 2005,4:203-205.
【54】邢丽华,刘剑波等.抑制NF-κB对人肺癌裸鼠移植瘤生长及血管生成的影响.肿瘤防治研究, 2005, 32:392-394.
【55】朱自路,程志祥等.重组腺病毒ΔN IκBα的构建及其对A549细胞中NF2κB活性的抑制.细胞与分子免疫学杂志, 2005,21(2):171-174.
【56】张建,徐永健等.转染IκBα基因抑制NF-κB活性对A549细胞侵袭行为的影响.癌症, 2008,27(7)710- 715.
【1】Coudert JD, Held W. The role of the NKG2D receptor for tumor immunity. Seminars in cancer biology, 2006,16:333-343.
【2】Chalupny NJ,Sutherland CL, et al. ULBP4 is a novel ligand for human NKG2D. Biochem Biophys Res Commum, 2003,305(1):129-135.
【3】Cao W, He W. UL16 binding proteins. Immunobiology, 2004,209(3):283-290.
【4】Borchers MT,Harris NL, et al. NKG2D ligands are expressed on stressed human airway epithelial cells. Am J Physiol Lung Cell Mol Physiol, 2006,292(2):L222-231.
【5】Pende D, Rivera P, Marcenaro S, et al. Major histocompatibility complex class I-related chain A and UL16-binding protein expression on tumor cell lins of different histotypes:analysis of tumor susceptibility to NKG2D-dependent natural killer cell cytotoxicity. Cancer Res, 2002,62(21):6178-6186.
【6】Zamai L, Ponti C, Mirandola P, et al. NK cells and cancer. J Immunol, 2007, 78:4011-6.
【7】Smyth MJ, Swann J, Cretney E, et al. NKG2D function protects the host from tumor initiation. The journal of Experimental medicine, 2005, 202:583-588.
【8】Schwechheimer C, Bevan MW, et al. The regulation of transcription activity in plants. Trends Plant Sci, 1998, 3:378-382.
【9】陈俊,王宗阳.植物MYB类转录因子研究进展.植物生理与分子生物学学报, 2002, 28(2):81-88.
【10】刘淑敏,朱瑞良等.转录因子靶基因的鉴定.植物生理学通讯. 2007, 43(2)333-340.
【11】Gopalakrishnan M. Venkataraman, et al. Promoter Region Architecture and Transcriptional Regulation of the Genes for the MHC Class I-Related Chain A and B Ligands of NKG2D. The Journal of Immunology 2007, 178: 961-969.
【12】Alejandro Lo′pez-Soto?1, et al. Transcriptional Regulation of ULBP1 ,a Human Ligand of the NKG2D Receptor. The journal of biological chemistry, 2006, 281(41):30419-30431.
【13】Gopalakrishnan M. Venkataraman, Dominic Suciu, et al. Promoter Region Architecture and Transcriptional Regulation of the Genes for the MHC Class I-Related Chain A and B Ligands of NKG2D. The Journal of Immunology, 2007, 178: 961-969.
【14】James E. Butler, Mikel B. Moore,Steven R. Presnell, et al. Proteasome Regulation of ULBP1 Transcription. The Journal of Immunology, 2009, 182: 6600-6609.
【15】杨聚荣,何娅妮等.人NaDC1基因启动子序列转录调控元件的初步分析。第三军医大学学报, 2007, 29(18):1787-1789. .
【1】Bartkova J, HorejsíZ, Koed K. et al. DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature. 2005;434:864-70
【2】Bartek J, Lukas J, Bartkova J. DNA damage response as an anti-cancer barrier: damage threshold and the concept of 'conditional haploinsufficiency'. Cell Cycle. 2007;6(19):2344-7
【3】Stephan Gasser, Sandra Orsulic, Eric J. Brown, and David H. Raulet. The DNA damage pathway regulates innate immune system ligands for the NKG2D receptor. Nature. 2005.436: 1186-1190.
【4】Coudert JD, Held W. The role of the NKG2D receptor for tumor immunity. Seminars in cancer biology. 2006;16:333-343
【5】Smyth MJ, Swann J, Cretney E, et al. NKG2D function protects the host from tumor initiation. The journal of Experimental medicine. 2005.202:583-588
【6】Gasser S, Raulet DH. Activation and self-tolerance of naural killer cells. Immunol Rev. 2006.214:130-42
【7】Zamai L, Ponti C, Mirandola P, et al. NK cells and cancer. J Immunol. 2007.178:4011-6
【8】Hayakawa Y, Smyth MJ. NKG2D and cytotoxic effector function in tumor immune surveillance. Seminars in Immunology. 2006.18:176-185
【9】Adelheid Cerwenka, New twist on the regulation of NKG2D lidand expression. J. Exp. Med. 2009,206:265-268
【10】Timothy J. Nice , Laurent Coscoy , and David H. Raulet. Posttranslational regulation of the NKG2D ligand Mult1 in response to cell stress. The Journal of Experimental Medicine.2009.206:287-298
【11】Stern-Ginossar , N. Human microRNAs regulate stress-induced immune responses mediated by the receptor NKG2D. Nat. Immunol.2008.9 : 1065 -1073
【2】Stephan Gasser. Activation and self-tolerance of natural killer cells.Immunological Reviews, 2006, 214:130-142.
【3】Ainhoa Arina1, Oihana Murillo1, et al. The combined actions of NK and T lymphocytes are ecessary to reject an EGFP+ mesenchymal tumor through mechanisms dependent on NKG2D and IFNγ. Cancer, 2007,121:1282-1295.
【4】Hans-Gustaf Ljunggren and Karl-Johan Malmberg, et al. Prospects for the use of NK cells in immunotherapy of human cancer. Immunology, 2007,7:329-339.
【5】Michael T. Borchers,Nathaniel L. Harris, et al. NKG2D ligands are expressed on stressed human airway epithelial cells. Physiol Lung Cell Mol Physiol, 2006,291:L222-L231.
【6】Steven J. Burgess, Kerima Maasho, et al. The NKG2D receptor: immunobiology and clinical Implications. Immunol Res, 2008, 40:18-34.
【7】Coudert JD, Held W,et al. The role of the NKG2D receptor for tumor immunity. Seminars in cancer biology, 2006;16:333-343.
【8】Robert A. Eagle, James A. Traherne, et al. Regulation of NKG2D Ligand Gene Expression, Human Immunology. 2006,67: 159-169.
【9】Gu¨nter Eisele, Jo¨rg Wischhusen, et al. TGF-βand metalloproteinases differentially suppress NKG2D ligand surface expression on malignant glioma cells. Brain ,2006, 129: 2416-2425.
【10】Noam Stern-Ginossar, Naama Elefant, et al. Host Immune System Gene Targeting by a Viral miRNA. Science, 2007,317:376-380.
【11】Stefan Bauer, Veronika Groh, et al. Activation of NK Cells and T Cells by NKG2D, a Receptor for Stress-Inducible MICA. Science, 1999, 285: 727-729.
【12】Cinzia Fionda,Alessandra Soriani, et al. Heat Shock Protein-90 Inhibitors Increase MHC Class I-Related Chain A and B Ligand Expression on Multiple Myeloma Cells and Their Ability to Trigger NK Cell Degranulation. The Journal of Immunology, 2009, 183: 4385-4394.
【13】Muzammel Haque, Keiji Ueda, Kazushi Nakano, et al. Major histocompatibility complex class I molecules are down-regulated at the cell surface by the K5 protein encoded by Kaposi’s sarcoma-associated herpesvirus/human herpesvirus-8. Journal of General Virology, 2001, 82:1175-1180.
【14】Manuel A. Friese,Jo¨rg Wischhusen, et al. RNA Interference Targeting Transforming Growth Factor-βEnhances NKG2D Mediated Antiglioma Immune Response, Inhibits Glioma Cell Migration and Invasiveness, and Abrogates Tumorigenicity In vivo. Cancer Research, 2004,64: 7596-7603.
【15】Daphna Nachmani, Noam Stern-Ginossar, et al. Diverse Herpesvirus MicroRNAs Target the Stress-Induced Immune Ligand MICB to Escape Recognition by Natural Killer Cells. Cell Host & Microbe, 2009, 5:376-385.
【16】Noam Stern-Ginossar,Naama Elefant, Albert Zimmermann, et al. Host Immune System Gene Targeting by a Viral miRNA. Science, 2007,317:376-380.
【17】Noam Stern-Ginossar, Chamutal Gur, et al. Human microRNAs regulate stress-induced immune responses mediated by the receptor NKG2D. Nature Immunology, 2008,9:1065-1073.
【18】Zamai L, Ponti C, Mirandola P, et al. NK cells and cancer. Immunol, 2007,178:4011-6.
【19】Smyth MJ, Swann J, Cretney E, et al. NKG2D function protects the host from tumor initiation. The journal of Experimental medicine, 2005,202:583-588.
【20】Jun Wu, Yaoli Song, Alexander B. H. Bakker, et al. An Activating Immunoreceptor Complex Formed by NKG2D and DAP10. Science, 1999, 285:730-732.
【21】Stephan Gasser, Sandra Orsulic, et al. The DNA damage pathway regulates innate immune system ligands for the NKG2D receptor. Nature, 2005,436: 11860-1190.
【22】Stephan Gasser and David H. Raulet. The DNA Damage Response Arouses the Immune System. Cancer Res, 2006, 66(8):3959-3962.
【23】Stephan Gasser, et al. DNA damage response and development of targeted cancer treatments. Annals of Medicine, 2007,39: 457-464.
【24】Stephan Gasser, David Raulet. The DNA damage response, immunity and cancer. Seminars in Cancer Biology, 2006,16: 344-347.
【25】Bartkova J, HorejsíZ, Koed K., et al. DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature, 2005,434:864-70.
【26】Bartek J, Lukas J, Bartkova J. DNA damage response as an anti-cancer barrier: damage threshold and the concept of 'conditional haploinsufficiency'. Cell Cycle, 2007,6(19):2344-7.
【27】Chauhan D,Hideshima T,Anderson KC. Proteasome inhibition in multiple myeloma:therapeutic implication. Annu Rev Pharmacol Toxicol, 2005,45:465-476.
【28】Gopalakrishnan M. Venkataraman, Dominic Suciu, et al. Promoter Region Architecture and Transcriptional Regulation of the Genes for the MHC Class I-Related Chain A and B Ligands of NKG2D. The Journal of Immunology, 2007, 178: 961-969.
【29】丁芳,吕茂民.猪内源性反转录病毒5′非编码区启动子活性的分析.中国农业科学2007,40(2):379-384.
【30】康鲁东,吴伟芳.人前列腺特异性膜抗原基因启动子/增强子表达载体的构建及组织特异性鉴定.中国病理生理杂志,2007,23 (1) : 120 -123.
【31】卜友泉,宋方洲.人NFBD1启动子的鉴定与初步分析.中国生物化学与分子生物学报, 2007,23 (8) :631-637.
【32】张健,陈苏宁.人NDRG2启动子的克隆与活性鉴定.生物技术通讯,2007,18:009-011.
【33】单佑安,刘庆等. MD22基因启动子区- 1064、- 1625 SNP对启动子活性的影响.第三军医大学学报,2007,29,3:185-187.
【34】李新玲,杨传平. rd29A启动子的克隆及提高烟草抗逆性的研究.分子植物育种,2007,5 (1 ):37-42.
【35】张素萍,徐乃玉,童建.顺铂作用HeLa细胞的蛋白质组学研究.中华肿瘤防治杂志,2008,15(3):174-177.
【36】刘华英,罗晓敏,李夏雨等.过表达E2F6基因抑制BRD7基因启动子活性. Chinese Journal of Biochemistry and Molecular Biology, 2006,22:886-893.
【37】Xue Li-xiang,Weng Mo,Zhang Zong-yu et al. Optimization of reporter gene assay:several factors influencing detection of promoter activity. Chin Med J,2007,120(11):965-969.
【38】朱玉萍,何超,朱洪波等.结肠癌细胞获得性5氟尿嘧啶耐药的机制研究. Chinese Journal of Pathophysiology,2007,23(10):2007-2011.
【39】Robert A. Eagle, James A. Traherne, et al. .Regulation of NKG2D Ligand Gene Expression.Human Immunology.2006,67:159-169.
【40】Mair Thomas, Jessica M. Boname, et al. Down Regulation of NKG2D and NKp80 ligands by Kaposi’s arcoma-associated herpesvirus K5 protects against NK cell cytotoxicity. PNAS, 2008,105:1656-1661.
【41】Alejandro Lo′pez-Soto, et al. Transcriptional Regulation of ULBP1, a Human Ligand of the NKG2D Receptor. The Journal of Biological Chemistry, 2006,281:30419-30430.
【42】Cai Zhang, Yiping Wang, Zhixia Zhou, et al. Sodium butyrate upregulates expression of NKG2D ligand MICA/B in HeLa and HepG2 cell lines and increases their susceptibility to NK lysis. Cancer Immunol Immunother, 2009,58:1275-1285.
【43】易彤波,杨连粤等. Caspase-8在5氟尿嘧啶诱导肝癌细胞凋亡中的作用.中国普通外科杂志,2002,17:171-172.
【44】James E. Butler, Mikel B. Moore,Steven R. Presnell, et al.Proteasome Regulation of ULBP1 Transcription. The Journal of Immunology, 2009,182: 6600 -6609.
【45】J Bartek, J Bartkova and J Lukas, et al. DNA damage signalling guards against activated oncogenes and tumour Progression. Oncogene, 2007,26:7773-7779.
【46】Adelheid Cerwenka, et al. New twist on the regulation of NKG2D lidand expression. Exp. Med, 2009,206:265-268.
【47】Timothy J. Nice , Laurent Coscoy, et al. Posttranslational regulation of the NKG2D ligand Mult1 in response to cell stress. The Journal of Experimental Medicine, 2009,206:287-298.
【48】Yizhou Zou, Effect of Human Cytomegalovirus on Expression of MHC Class I-Related Chains A. The Journal of Immunology, 2005,174:3098-3104.
【49】James E. Butler, Mikel B. Moore, Proteasome Regulation of ULBP1 Transcription. The Journal of Immunology, 2009, 182: 6600 -6609.
【50】Luciana L. Molinero, Mercedes B. Fuertes, et al. NF-κB Regulates Expression of the MHC Class I-Related Chain A Gene in Activated T Lymphocytes. The Journal of Immunology, 2004, 173: 5583-5590.
【51】张惠兰,张珍祥,徐永健. NF-κB圈套寡核苷酸促进肺癌细胞.A549凋亡的作用中国病理生理杂志.2004,20 (12) :2294-2298.
【52】廖品琥,黄冰等.白细胞介素-1β激活核转录因子-κB介导A549细胞分泌白细胞介素-8的研究.临床麻醉学杂志, 2007,23:43-45.
【53】邢丽华,樊再雯,刘剑波.核因子-κB抑制剂联合顺铂对A549细胞株的影响.中国呼吸与危重监护杂志, 2005,4:203-205.
【54】邢丽华,刘剑波等.抑制NF-κB对人肺癌裸鼠移植瘤生长及血管生成的影响.肿瘤防治研究, 2005, 32:392-394.
【55】朱自路,程志祥等.重组腺病毒ΔN IκBα的构建及其对A549细胞中NF2κB活性的抑制.细胞与分子免疫学杂志, 2005,21(2):171-174.
【56】张建,徐永健等.转染IκBα基因抑制NF-κB活性对A549细胞侵袭行为的影响.癌症, 2008,27(7)710- 715.
【1】Coudert JD, Held W. The role of the NKG2D receptor for tumor immunity. Seminars in cancer biology, 2006,16:333-343.
【2】Chalupny NJ,Sutherland CL, et al. ULBP4 is a novel ligand for human NKG2D. Biochem Biophys Res Commum, 2003,305(1):129-135.
【3】Cao W, He W. UL16 binding proteins. Immunobiology, 2004,209(3):283-290.
【4】Borchers MT,Harris NL, et al. NKG2D ligands are expressed on stressed human airway epithelial cells. Am J Physiol Lung Cell Mol Physiol, 2006,292(2):L222-231.
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