肿瘤相关miRNAs对树突细胞寿命与功能的调控
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摘要
树突状细胞(DCs)是免疫系统中功能最强的抗原呈递细胞，是连接固有免疫和获得性免疫的桥梁。在体内，它起着双重作用，既能调节免疫应答，又能引导免疫耐受。在肿瘤免疫中，树突状细胞发挥着重要的作用，一方面，DCs在抑制肿瘤生长中发挥重要作用，另一方面，肿瘤的生长同样也对DCs乃至整个免疫系统的功能有着极其深刻的影响。本论文主要探讨了肿瘤相关miRNAs及其靶基因对树突状细胞功能的调节作用，这些结果将对肿瘤及其免疫相关疾病的治疗产生重要影响。主要结果：
(1)通过建立体外肿瘤与树突状细胞共培养模型，运用基因芯片结合定量PCR，我们鉴定了在树突状细胞中与肿瘤相关的miRNAs,如miR-22,miR-128和miR-503。
(2)肿瘤相关miR-22和miR-503通过靶向YWHAZ和Bcl2信号途径调节树突状细胞的存活寿命。肿瘤可利用一系列的免疫抑制手段，例如减少树突状细胞的生存寿命，来减弱免疫反应并限制免疫疗效。我们发现肿瘤上调多个miRNA的表达，如miR-16-1、miR-22、miR-155和miR-503.这些肿瘤相关联的miRNA通过调控凋亡信号途径中的多个分子的表达来影响树灾状细胞的存活。特别地，miR-22靶向调控YWHAZ来干扰PI3K/Akt和MAPK信号途径，而miR-503则下调Bcl2的表达。肿癇相关联的树灾状细胞中miR-22和miR-503表达量上升的后果是树灾状细胞生存寿命的减少。因此，肿瘤相关联的miRNA可以通过靶向调控多种胞内信号分子使得肿瘤环境中的树突状细胞发生凋亡利用miR-22和miR-503的抑制剂可能是改善树灾状细胞抗肿瘤免疫治疗的一个新的策略。
(3)肿瘤相关miR-22通过靶向p38能够影响树灾状细胞的功能。p38MAPK作为MAPK信号通中中关键的一类，对于树灾状细胞的成熟及激活等都具有至关重要的调节作用。研究发现，在树突状细胞中，miR-22通过作用于p38的3'UTR来调节p38的表达，引起细胞因子IL-6分泌的增多，促使初naiveT细胞向Th17方向分化，增加了机体对抗肿瘤的能力。研究揭示了miR-22可能作为抵抗疾病特别是肿瘤的免疫治疗的靶分子．
(4) miR-128通过靶向p38调控树突状细胞中IL-6的产生。我们首先利用生物信息学的方法预测了p38可能受到一系列microRNA的调控,进一步利用双荧光素酶报告载体系统证实了miR-128可直接作用于p38基因的3'UTR并抑制p38的表达。而且,转染miR-128可以很显著地降低树突状细胞中p38的蛋白水平,进而引起细胞因子IL-6分泌的增多。这些研究结果为microRNA在自身免疫性疾病、肿瘤等多种疾病的发病与治疗研究中增添了新的依据。
Dendritic cells (DCs) are the strongest antigen presenting cells which connect innate immunity and adaptive immunity. They can regulate the immune response and induce the immune tolerance in vivo. DCs play an important role in tumor immunity. On one hand, DCs inhibit tumor growth. On the other hand, the growth of the tumor impairs the function of DCs and the whole immune system profoundly. In this thesis, we focus on the effect of certain tumor associated miRNAs and their target genes on the survival and function of DCs. Main findings:
(1) Identification of tumor associated miRNAs in dendritic cells. Through microarray-chip, combined with RT-PCR, we have analyzed the up-and down-regulated miRNAs in tumor associated DCs, which are coclutured with tumor cells, and demonstrated several tumor associated miRNAs, such as miR-22, miR-128and miR-503.
(2) Tumor-associated miR-22and miR-503modulate the survival and longevity of dendritic cells by targeting YWHAZ and Bcl2signaling pathways. Tumors use a wide array of immunosuppressive strategies, such as reducing the longevity and survival of dendritic cells (DCs), to diminish immune responses and limit the effect of immunotherapy. We found that tumors upregulate the expression of multiple microRNAs (miRNAs), such as miR-16-1, miR-22, miR-155, and miR-503. These tumor-associated miRNAs influenced the survival and longevity of DCs by affecting the expression of multiple molecules that are associated with apoptotic signaling pathways. Specifically, miR-22targeted YWHAZ to interrupt the PI3K/Akt and MAPK signaling pathways, and miR-503downregulated Bcl2expression. The increased expression of miR-22and miR-503in the tumor-associated DCs causes the reduced survival and longevity of DCs. Thus, tumor-associated miRNAs can target multiple intracellular signaling molecules to cause the apoptosis of DCs in the tumor environment. Use of miR-22and miR-503as inhibitors may therefore represent a new strategy to improve DC-based immunothcrapies against tumors.
(3) Tumor-associated mir-22affects DCs' functions by targeting p38MAPK. p38, a critical molecule of the MAPK signaling pathway, has a crucial role in regulating the maturation and activation of DCs. We demonstrate that mir-22regulates P38's expression by acting on p38's3'-UTR. Transfection of miR-22increase the excretion of cytokine IL-6. DC transfected using miR-22may mediate the differentiation of naive T cell toward Th17cell. In vivo experiments demonstrate that miR-22can promote the immune ability against tumors. Thus, our research suggests that miR-22can be potentially acted as a targeting molecule for tumor immunotherapy.
(4) miR-128targets p38to regulate the production of IL-6in DCs. Combined with bioinformatics analysis, p38was predicted as potential target of series of microRNAs. In this study, using dual luciferase reporter assays, our results demonstrate that miR-128could repress p38expression by binding to the3UTR of p38in a direct and sequence-specific manner. Moreover, transfection of miR-128mimics significantly decrease the protein level of p38in dendritic cell, and promote production of cytokine IL-6. Furthermore, results obtained in this thesis provide a new evidence for the effect of microRNA on regulating tumor immunity.
In conclusion, tumor associated miRNAs may affect the survival and longevity and modulate the function of dendritic cells by targeting their targeting molecules. The results not only bring about profound impact on understanding the mechanisms of tumor incidence and development but also on the immunotherapy against tumors.
(1)通过建立体外肿瘤与树突状细胞共培养模型，运用基因芯片结合定量PCR，我们鉴定了在树突状细胞中与肿瘤相关的miRNAs,如miR-22,miR-128和miR-503。
(2)肿瘤相关miR-22和miR-503通过靶向YWHAZ和Bcl2信号途径调节树突状细胞的存活寿命。肿瘤可利用一系列的免疫抑制手段，例如减少树突状细胞的生存寿命，来减弱免疫反应并限制免疫疗效。我们发现肿瘤上调多个miRNA的表达，如miR-16-1、miR-22、miR-155和miR-503.这些肿瘤相关联的miRNA通过调控凋亡信号途径中的多个分子的表达来影响树灾状细胞的存活。特别地，miR-22靶向调控YWHAZ来干扰PI3K/Akt和MAPK信号途径，而miR-503则下调Bcl2的表达。肿癇相关联的树灾状细胞中miR-22和miR-503表达量上升的后果是树灾状细胞生存寿命的减少。因此，肿瘤相关联的miRNA可以通过靶向调控多种胞内信号分子使得肿瘤环境中的树突状细胞发生凋亡利用miR-22和miR-503的抑制剂可能是改善树灾状细胞抗肿瘤免疫治疗的一个新的策略。
(3)肿瘤相关miR-22通过靶向p38能够影响树灾状细胞的功能。p38MAPK作为MAPK信号通中中关键的一类，对于树灾状细胞的成熟及激活等都具有至关重要的调节作用。研究发现，在树突状细胞中，miR-22通过作用于p38的3'UTR来调节p38的表达，引起细胞因子IL-6分泌的增多，促使初naiveT细胞向Th17方向分化，增加了机体对抗肿瘤的能力。研究揭示了miR-22可能作为抵抗疾病特别是肿瘤的免疫治疗的靶分子．
(4) miR-128通过靶向p38调控树突状细胞中IL-6的产生。我们首先利用生物信息学的方法预测了p38可能受到一系列microRNA的调控,进一步利用双荧光素酶报告载体系统证实了miR-128可直接作用于p38基因的3'UTR并抑制p38的表达。而且,转染miR-128可以很显著地降低树突状细胞中p38的蛋白水平,进而引起细胞因子IL-6分泌的增多。这些研究结果为microRNA在自身免疫性疾病、肿瘤等多种疾病的发病与治疗研究中增添了新的依据。
Dendritic cells (DCs) are the strongest antigen presenting cells which connect innate immunity and adaptive immunity. They can regulate the immune response and induce the immune tolerance in vivo. DCs play an important role in tumor immunity. On one hand, DCs inhibit tumor growth. On the other hand, the growth of the tumor impairs the function of DCs and the whole immune system profoundly. In this thesis, we focus on the effect of certain tumor associated miRNAs and their target genes on the survival and function of DCs. Main findings:
(1) Identification of tumor associated miRNAs in dendritic cells. Through microarray-chip, combined with RT-PCR, we have analyzed the up-and down-regulated miRNAs in tumor associated DCs, which are coclutured with tumor cells, and demonstrated several tumor associated miRNAs, such as miR-22, miR-128and miR-503.
(2) Tumor-associated miR-22and miR-503modulate the survival and longevity of dendritic cells by targeting YWHAZ and Bcl2signaling pathways. Tumors use a wide array of immunosuppressive strategies, such as reducing the longevity and survival of dendritic cells (DCs), to diminish immune responses and limit the effect of immunotherapy. We found that tumors upregulate the expression of multiple microRNAs (miRNAs), such as miR-16-1, miR-22, miR-155, and miR-503. These tumor-associated miRNAs influenced the survival and longevity of DCs by affecting the expression of multiple molecules that are associated with apoptotic signaling pathways. Specifically, miR-22targeted YWHAZ to interrupt the PI3K/Akt and MAPK signaling pathways, and miR-503downregulated Bcl2expression. The increased expression of miR-22and miR-503in the tumor-associated DCs causes the reduced survival and longevity of DCs. Thus, tumor-associated miRNAs can target multiple intracellular signaling molecules to cause the apoptosis of DCs in the tumor environment. Use of miR-22and miR-503as inhibitors may therefore represent a new strategy to improve DC-based immunothcrapies against tumors.
(3) Tumor-associated mir-22affects DCs' functions by targeting p38MAPK. p38, a critical molecule of the MAPK signaling pathway, has a crucial role in regulating the maturation and activation of DCs. We demonstrate that mir-22regulates P38's expression by acting on p38's3'-UTR. Transfection of miR-22increase the excretion of cytokine IL-6. DC transfected using miR-22may mediate the differentiation of naive T cell toward Th17cell. In vivo experiments demonstrate that miR-22can promote the immune ability against tumors. Thus, our research suggests that miR-22can be potentially acted as a targeting molecule for tumor immunotherapy.
(4) miR-128targets p38to regulate the production of IL-6in DCs. Combined with bioinformatics analysis, p38was predicted as potential target of series of microRNAs. In this study, using dual luciferase reporter assays, our results demonstrate that miR-128could repress p38expression by binding to the3UTR of p38in a direct and sequence-specific manner. Moreover, transfection of miR-128mimics significantly decrease the protein level of p38in dendritic cell, and promote production of cytokine IL-6. Furthermore, results obtained in this thesis provide a new evidence for the effect of microRNA on regulating tumor immunity.
In conclusion, tumor associated miRNAs may affect the survival and longevity and modulate the function of dendritic cells by targeting their targeting molecules. The results not only bring about profound impact on understanding the mechanisms of tumor incidence and development but also on the immunotherapy against tumors.
引文
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