胰腺癌BxPC-3细胞上清液通过上调树突状细胞miRNA-146a的表达抑制其成熟及免疫功能的研究
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摘要
胰腺癌是一种高度恶性的肿瘤，其死亡率位居全部恶性肿瘤的第四位，在我国其发病率呈现出逐年上升的趋势。由于手术治疗及传统的放化疗并不能明显提高患者的5年生存率，因此肿瘤免疫治疗逐渐成为胰腺癌治疗研究的热点。然而，因为肿瘤免疫逃避机制的存在，肿瘤免疫治疗往往不能达到令人满意的效果。因此，以肿瘤免疫及相关机制为对象的研究成为目前攻克肿瘤免疫耐受及免疫逃避，实现有效治疗的重要手段。
树突状细胞（dendritic cell DC)是目前发现的功能最强大的抗原递呈细胞，在抗原递呈、T细胞活化及免疫耐受方面发挥着重要的作用。研究发现，肿瘤细胞可逃避免疫系统而存活，同时建立肿瘤微环境来抑制DC的成熟及相关的免疫功能；胰腺癌细胞上清液可明显抑制DC的分化和抗原递呈功能；胰腺癌患者血清中的DC数量和功能亦明显受抑，但其中详细的机制仍然不十分明了。综上所述，明确胰腺癌微环境下DC的受损机制成为克服肿瘤免疫逃避、提高免疫治疗的重要前提条件。
微小RNA（miRNA）是一类由20-23个核苷酸组成的内源性非编码小分子单链RNA,能够识别特定的目标mRNA，参与转录后水平的基因调控，在机体的正常生理活动和各种疾病的发生、发展过程中都起着重要的调节作用。研究表明，miRNA-146a在免疫反应、炎症反应以及细胞的增殖、分化、成熟过程中都起着十分重要的调节作用。最新的研究显示，miRNA-146a对DC的增殖分化及成熟也起着重要的调控作用。
基于上述理论，本实验采用恶性程度较高的胰腺癌BxPC-3细胞系为研究对象，探讨在胰腺癌BxPC-3细胞上清液（BxPC-3-conditioned medium, BxCM）的作用下，DC内miRNA-146a的变化及其对DC成熟和功能的影响，以揭示胰腺癌微环境抑制DC的相关分子机制。
第一部分人外周血来源DC的制备及BxCM对其分化成熟抑制作用的研究
目的：体外分离培养人外周血来源的DC，观察BxCM对DC分化成熟的抑制作用。
方法：取健康志愿者外周血，使用淋巴细胞分离液分离获得CD14+单核细胞。体外联合应用重组人粒细胞集落刺激因子（GM-CSF）及白细胞介素4（IL-4）诱导其分化为DC，应用肿瘤坏死因子α（TNF-α）促进其成熟。利用人胰腺癌BxPC-3细胞系提取BxCM，与上述细胞因子共同诱导CD14+单核细胞。流式细胞仪检测DC分化成熟相关抗原分子的表达情况，观察BxCM对DC分化成熟的抑制作用。
结果：体外成功分离培养出人CD14+单核细胞，并诱导其分化成为成熟的DC；与常规培养组相比，BxCM干预下诱导的DC，其CD14仍维持在高水平（P＜0.05），而CD1a、CD80、CD83、CD86及HLA-DR等DC成熟相关表面抗原的表达则显著降低（P＜0.05）。
结论：BxCM能够显著抑制DC表面抗原的表达，进而阻碍CD14+单核细胞向DC的分化及DC的成熟。
第二部分BxCM对DC内miRNA-146a及Smad4蛋白表达的影响
目的：研究BxCM干预下DC内miRNA-146a及Smad4蛋白表达水平的变化，探讨miRNA-146a与Smad4蛋白表达之间的关系，为进一步阐明DC受抑机制提供理论依据。
方法：通过QRT-PCR法比较常规培养组与BxCM干预组中DC内miRNA-146a表达水平的变化；通过QRT-PCR及Western-blot法比较两组DC内Smad4基因mRNA与蛋白表达变化。同时应用脂质体2000（Lip2000）将anti-miRNA-146a寡核苷酸或非特异性寡核苷酸片段转染至DC内沉默miRNA-146a的表达，以探讨miRNA-146a与Smad4蛋白表达之间的关系。
结果：与常规培养组中DC相比，BxCM干预组中DC内miRNA-146a的表达均显著增高（P＜0.05）；与此相反，Smad4的mRNA与蛋白表达则明显低于常规培养组（P＜0.05）。同时，当miRNA-146a的表达被有效沉默后，常规组及BxCM干预组中DC内Smad4的mRNA与蛋白表达的水平均明显上调（P＜0.05）。
结论：DC内miRNA-146a可负向调节Smad4蛋白的表达。BxCM在抑制DC分化成熟的同时，能够显著上调DC内miRNA-146a的表达水平；而作为miRNA-146a负向调控的靶基因之一，Smad4的表达水平则明显降低。因此，BxCM有可能通过miRNA-146a-Smad4介导的信号通路抑制DC分化成熟。
第三部分下调BxCM诱导的DC内异常增高的miRNA-146a水平对DC成熟及免疫功能的影响
目的：研究下调BxCM干预组中DC内miRNA-146a的表达水平对DC分化成熟及免疫功能的影响，探讨胰腺癌微环境下DC成熟及免疫功能受抑制的详细机制，为DC介导的抗胰腺癌免疫治疗提供必要的理论及实验依据。
方法：应用Lip2000将anti-miRNA-146a寡核苷酸转染至BxCM干预组的DC内，以沉默miRNA-146a的表达。流式细胞仪检测各组DC分化成熟相关抗原的表达变化情况；酶联免疫吸附实验（ELISA）测定各组DC的IL-12分泌水平。利用胰腺癌BxPC-3细胞的裂解物制备全肿瘤特异性抗原并负载DC，各组致敏的DC按DC:T淋巴细胞为1:10的比例混合培养（混合淋巴细胞反应， MLR）。24小时后ELISPOT法测定各组干扰素-γ（IFN-γ）分泌水平，ELISA测定各组T淋巴细胞IL-12的分泌水平。5天后MTS法测定各组淋巴细胞增殖情况；乳酸脱氢酶(LDH)释放实验观察各组DC体外诱导的主动特异性细胞毒T淋巴细胞（CTL）反应对BxPC-3细胞的杀伤作用。
结果：与BxCM干预组中DC相比，下调DC内miRNA-146a的表达水平能显著增加DC表面分子CD1a、CD80、CD83、CD86及HLA-DR的表达（P＜0.05），但仍低于正常水平。同样，抑制DC内miRNA-146a的过度表达虽然不能完全恢复其刺激T细胞增殖及激活CTL的能力，但是与BxCM干预组中DC相比，其免疫功能显著提高（P＜0.05）。
结论：体外BxCM对DC成熟及免疫功能的抑制作用在一定程度上是通过上调DC内miRNA-146a的表达水平来实现的。
Pancreatic cancer is one of the most fatal malignant tumors and the fourthcause of cancer-related death. The incidence of pancreatic cancer in China is rising year by year. Like other solid tumors, surgery alone is not the ultimate treatment for this disease. The limited effect and toxicity of standard chemotherapy and radiotherapy make immunotherapy an attractive alternative. However, the immunotherapy is not successful due to the existence of mechanisms of tumor immunologic escape. So the study of the mechanism regarding tumor immunologic escape is of importance.
Dendritic cells are the most potent professional antigen-presenting cells (APCs) in the immune system, and they can activate intensive T lymphocyte response against tumors. Tumor cells can evade immune surveillance and establish an immunosuppressive environment that inhibits maturation and function of DC in vitro. Previous studies have found that differentiation and antigen presentation function of DCs are suppressed by pancreatic cancer cell-conditioned medium in vitro;
moreover, the number and function of circulating DCs are also impaired in pancreatic cancer patients. But, the detailed mechanisms involved in the effect of pancreatic cancer on DCs remain unclear.
MicroRNA (miRNA) is a class of small (20–23nucleotides) endogenous non-coding RNA, which negatively regulates gene expression by inhibiting translation or degradation of mRNA. Furthermore, bioinformatics studies have demonstrated that one miRNA can regulate hundreds of mRNA targets, which could be implicated in almost all physiological and pathological pathways. More recently, studies have indicated that miRNA-146a, a miRNA, can play an important role in m ediating a wide spectrum of biological processes, such as immune and inflammatory response, cell proliferation, differentiation, apoptosis as well as tumorigenesis.
Moreover, miRNA-146a has been suggested to be associated with DC differentiation and maturation.
As BxPC-3is an extremely metastatic human pancreatic cancer cell line,BxPC-3-conditioned medium (BxCM) was used as pancreatic cancer-conditionedmedium. The aim of this study was to investigate the expression of miRNA-146a inDCs induced by pancreatic cancer cell conditioned medium and its effect on DCmaturation and function.
Part1The generation of peripheral blood monocyte-derived DC andthe inhibition of BxCM on the phenotypic maturation of DC
Objective: To generate the human peripheral blood monocyte-derived DC. Toinvestigate the inhibitory effect of BxCM on the differentiation and maturation of DC.
Methods: Peripheral blood mononuclear cells were obtained from healthy donorsusing lymphoprep. The monocytes were cultured with GM-CSF and IL-4or GM-CSFplus IL-4plus BxCM in vitro. For mature DC, Human TNF-α was added. To study theinhibitory effect of BxCM on the differentiation and maturation of DC, cell surfacemarkers for DC differentiation and maturation were analyzed using flow cytometry.
Results: Human CD14+monocytes and DC were successfully generated in vitro.The expression of CD14+in BxCM-treated group were still higher than that in normalgroup (P＜0.05). On the country, the expression of mature phenotypes, such as CD1a,CD80, CD83, CD86and HLA-DR in BxCM-treated group were significantly lowerthan those in normal group (P＜0.05).
Conclusion: BxCM could inhibit the differentiation of DC from CD14+monocytesand DC maturation by suppressing the expression of typical phenotype.
Part2The effect of BxCM on the expression of miRNA-146a andSmad4protein in DC
Objective: To investigate whether the expression of miRNA-146a and Smad4were changed in BxCM-treated DCs. To further determine the role of miRNA-146a onthe expression of Smad4protein. To offer the basic theory for the explaining the mechanism that how DC were inhibited.
Methods: QRT-PCR and Western-blot assay were used to investigate the changeof miRNA-146a and Smad4expression in BxCM-treated DCs. To further determine therole of miRNA-146a on Smad4expression, BxCM-treated DCs and DCs weretransfected with miRNA-146a inhibitor or negative control miRNA inhibitor (NCinhibitor) using Lip2000and the expression of Smad4was assessed using QRT-PCRand Western blot assays.
Results: The expression levels of miRNA-146a were notably up-regulated byBxCM in DCs compared with normal ones (P＜0.05). However, the protein level ofSmad4in BxCM-treated DCs was significantly lower than those in normal DCs (P＜0.05). Meanwhile, decreased expression of miRNA-146a caused by miRNA-146ainhibitor recovered the reduced expression of Smad4in BxCM-treated DCs and normalDCs (P＜0.05).
Conclusion: miRNA-146a negatively regulates the Smad4gene expression both inBxCM-treated DCs and normal DCs. BxCM enhanced the expression level ofmiRNA-146a and inhibited the expression of Smad4, which may contribute to its abilityto suppress maturation and function of DCs.
Part3The effects of blocking elevated miRNA-146a in BxCM-inducedDC on the maturation and immune function of DC
Objective: To investigate the role of miRNA-146a on BxCM-mediated DCphenotype and immune function change. To study the detailed mechanisms involved inthe effect of pancreatic cancer on DCs and offer the necessary theory forimmunotherapy.
Methods: miRNA-146a inhibitor or NC inhibitor were transfected in theBxCM-treated mDCs. The expressions of cell surface markers and IL-12were testedusing flow cytometry and ELISA assay. DCs were loaded with whole tumor cell antigenof BxPC-3cells. The antigen-loaded mDCs were incubated with T lymphocyte cells at aDC/T cell ratio of1:10. Interferon (INF)-γ and IL-12secretion levels were examined at24h after cell mixing using Human IFN-γ ELISPOT Kit and Human IL-12ELISAassay Kit. T lymphocyte proliferation was determined using the MTS assay afterincubation for5days. CTL response was used to investigate the effect of DCs on theactivity of tumor specific CTLs induced in vitro.
Results: Inhibition of elevated miRNA-146a significantly increased the expressionof CD1a, CD86, CD80, CD83, and HLA-DR on BxCM-treated DCs (P＜0.05),although still less than untreated DCs. There was a notably increased T cell proliferationrate and stronger CTL response in miRNA-146a inhibitor group compared with that inBxCM-treated group, although still lower than that in normal group (P＜0.05).
Conclusion: BxCM reduced phenotypic maturation and the ability of the DCs toactivate the immune response, which is partly through up-regulating miRNA-146aexpression in DCs.
树突状细胞（dendritic cell DC)是目前发现的功能最强大的抗原递呈细胞，在抗原递呈、T细胞活化及免疫耐受方面发挥着重要的作用。研究发现，肿瘤细胞可逃避免疫系统而存活，同时建立肿瘤微环境来抑制DC的成熟及相关的免疫功能；胰腺癌细胞上清液可明显抑制DC的分化和抗原递呈功能；胰腺癌患者血清中的DC数量和功能亦明显受抑，但其中详细的机制仍然不十分明了。综上所述，明确胰腺癌微环境下DC的受损机制成为克服肿瘤免疫逃避、提高免疫治疗的重要前提条件。
微小RNA（miRNA）是一类由20-23个核苷酸组成的内源性非编码小分子单链RNA,能够识别特定的目标mRNA，参与转录后水平的基因调控，在机体的正常生理活动和各种疾病的发生、发展过程中都起着重要的调节作用。研究表明，miRNA-146a在免疫反应、炎症反应以及细胞的增殖、分化、成熟过程中都起着十分重要的调节作用。最新的研究显示，miRNA-146a对DC的增殖分化及成熟也起着重要的调控作用。
基于上述理论，本实验采用恶性程度较高的胰腺癌BxPC-3细胞系为研究对象，探讨在胰腺癌BxPC-3细胞上清液（BxPC-3-conditioned medium, BxCM）的作用下，DC内miRNA-146a的变化及其对DC成熟和功能的影响，以揭示胰腺癌微环境抑制DC的相关分子机制。
第一部分人外周血来源DC的制备及BxCM对其分化成熟抑制作用的研究
目的：体外分离培养人外周血来源的DC，观察BxCM对DC分化成熟的抑制作用。
方法：取健康志愿者外周血，使用淋巴细胞分离液分离获得CD14+单核细胞。体外联合应用重组人粒细胞集落刺激因子（GM-CSF）及白细胞介素4（IL-4）诱导其分化为DC，应用肿瘤坏死因子α（TNF-α）促进其成熟。利用人胰腺癌BxPC-3细胞系提取BxCM，与上述细胞因子共同诱导CD14+单核细胞。流式细胞仪检测DC分化成熟相关抗原分子的表达情况，观察BxCM对DC分化成熟的抑制作用。
结果：体外成功分离培养出人CD14+单核细胞，并诱导其分化成为成熟的DC；与常规培养组相比，BxCM干预下诱导的DC，其CD14仍维持在高水平（P＜0.05），而CD1a、CD80、CD83、CD86及HLA-DR等DC成熟相关表面抗原的表达则显著降低（P＜0.05）。
结论：BxCM能够显著抑制DC表面抗原的表达，进而阻碍CD14+单核细胞向DC的分化及DC的成熟。
第二部分BxCM对DC内miRNA-146a及Smad4蛋白表达的影响
目的：研究BxCM干预下DC内miRNA-146a及Smad4蛋白表达水平的变化，探讨miRNA-146a与Smad4蛋白表达之间的关系，为进一步阐明DC受抑机制提供理论依据。
方法：通过QRT-PCR法比较常规培养组与BxCM干预组中DC内miRNA-146a表达水平的变化；通过QRT-PCR及Western-blot法比较两组DC内Smad4基因mRNA与蛋白表达变化。同时应用脂质体2000（Lip2000）将anti-miRNA-146a寡核苷酸或非特异性寡核苷酸片段转染至DC内沉默miRNA-146a的表达，以探讨miRNA-146a与Smad4蛋白表达之间的关系。
结果：与常规培养组中DC相比，BxCM干预组中DC内miRNA-146a的表达均显著增高（P＜0.05）；与此相反，Smad4的mRNA与蛋白表达则明显低于常规培养组（P＜0.05）。同时，当miRNA-146a的表达被有效沉默后，常规组及BxCM干预组中DC内Smad4的mRNA与蛋白表达的水平均明显上调（P＜0.05）。
结论：DC内miRNA-146a可负向调节Smad4蛋白的表达。BxCM在抑制DC分化成熟的同时，能够显著上调DC内miRNA-146a的表达水平；而作为miRNA-146a负向调控的靶基因之一，Smad4的表达水平则明显降低。因此，BxCM有可能通过miRNA-146a-Smad4介导的信号通路抑制DC分化成熟。
第三部分下调BxCM诱导的DC内异常增高的miRNA-146a水平对DC成熟及免疫功能的影响
目的：研究下调BxCM干预组中DC内miRNA-146a的表达水平对DC分化成熟及免疫功能的影响，探讨胰腺癌微环境下DC成熟及免疫功能受抑制的详细机制，为DC介导的抗胰腺癌免疫治疗提供必要的理论及实验依据。
方法：应用Lip2000将anti-miRNA-146a寡核苷酸转染至BxCM干预组的DC内，以沉默miRNA-146a的表达。流式细胞仪检测各组DC分化成熟相关抗原的表达变化情况；酶联免疫吸附实验（ELISA）测定各组DC的IL-12分泌水平。利用胰腺癌BxPC-3细胞的裂解物制备全肿瘤特异性抗原并负载DC，各组致敏的DC按DC:T淋巴细胞为1:10的比例混合培养（混合淋巴细胞反应， MLR）。24小时后ELISPOT法测定各组干扰素-γ（IFN-γ）分泌水平，ELISA测定各组T淋巴细胞IL-12的分泌水平。5天后MTS法测定各组淋巴细胞增殖情况；乳酸脱氢酶(LDH)释放实验观察各组DC体外诱导的主动特异性细胞毒T淋巴细胞（CTL）反应对BxPC-3细胞的杀伤作用。
结果：与BxCM干预组中DC相比，下调DC内miRNA-146a的表达水平能显著增加DC表面分子CD1a、CD80、CD83、CD86及HLA-DR的表达（P＜0.05），但仍低于正常水平。同样，抑制DC内miRNA-146a的过度表达虽然不能完全恢复其刺激T细胞增殖及激活CTL的能力，但是与BxCM干预组中DC相比，其免疫功能显著提高（P＜0.05）。
结论：体外BxCM对DC成熟及免疫功能的抑制作用在一定程度上是通过上调DC内miRNA-146a的表达水平来实现的。
Pancreatic cancer is one of the most fatal malignant tumors and the fourthcause of cancer-related death. The incidence of pancreatic cancer in China is rising year by year. Like other solid tumors, surgery alone is not the ultimate treatment for this disease. The limited effect and toxicity of standard chemotherapy and radiotherapy make immunotherapy an attractive alternative. However, the immunotherapy is not successful due to the existence of mechanisms of tumor immunologic escape. So the study of the mechanism regarding tumor immunologic escape is of importance.
Dendritic cells are the most potent professional antigen-presenting cells (APCs) in the immune system, and they can activate intensive T lymphocyte response against tumors. Tumor cells can evade immune surveillance and establish an immunosuppressive environment that inhibits maturation and function of DC in vitro. Previous studies have found that differentiation and antigen presentation function of DCs are suppressed by pancreatic cancer cell-conditioned medium in vitro;
moreover, the number and function of circulating DCs are also impaired in pancreatic cancer patients. But, the detailed mechanisms involved in the effect of pancreatic cancer on DCs remain unclear.
MicroRNA (miRNA) is a class of small (20–23nucleotides) endogenous non-coding RNA, which negatively regulates gene expression by inhibiting translation or degradation of mRNA. Furthermore, bioinformatics studies have demonstrated that one miRNA can regulate hundreds of mRNA targets, which could be implicated in almost all physiological and pathological pathways. More recently, studies have indicated that miRNA-146a, a miRNA, can play an important role in m ediating a wide spectrum of biological processes, such as immune and inflammatory response, cell proliferation, differentiation, apoptosis as well as tumorigenesis.
Moreover, miRNA-146a has been suggested to be associated with DC differentiation and maturation.
As BxPC-3is an extremely metastatic human pancreatic cancer cell line,BxPC-3-conditioned medium (BxCM) was used as pancreatic cancer-conditionedmedium. The aim of this study was to investigate the expression of miRNA-146a inDCs induced by pancreatic cancer cell conditioned medium and its effect on DCmaturation and function.
Part1The generation of peripheral blood monocyte-derived DC andthe inhibition of BxCM on the phenotypic maturation of DC
Objective: To generate the human peripheral blood monocyte-derived DC. Toinvestigate the inhibitory effect of BxCM on the differentiation and maturation of DC.
Methods: Peripheral blood mononuclear cells were obtained from healthy donorsusing lymphoprep. The monocytes were cultured with GM-CSF and IL-4or GM-CSFplus IL-4plus BxCM in vitro. For mature DC, Human TNF-α was added. To study theinhibitory effect of BxCM on the differentiation and maturation of DC, cell surfacemarkers for DC differentiation and maturation were analyzed using flow cytometry.
Results: Human CD14+monocytes and DC were successfully generated in vitro.The expression of CD14+in BxCM-treated group were still higher than that in normalgroup (P＜0.05). On the country, the expression of mature phenotypes, such as CD1a,CD80, CD83, CD86and HLA-DR in BxCM-treated group were significantly lowerthan those in normal group (P＜0.05).
Conclusion: BxCM could inhibit the differentiation of DC from CD14+monocytesand DC maturation by suppressing the expression of typical phenotype.
Part2The effect of BxCM on the expression of miRNA-146a andSmad4protein in DC
Objective: To investigate whether the expression of miRNA-146a and Smad4were changed in BxCM-treated DCs. To further determine the role of miRNA-146a onthe expression of Smad4protein. To offer the basic theory for the explaining the mechanism that how DC were inhibited.
Methods: QRT-PCR and Western-blot assay were used to investigate the changeof miRNA-146a and Smad4expression in BxCM-treated DCs. To further determine therole of miRNA-146a on Smad4expression, BxCM-treated DCs and DCs weretransfected with miRNA-146a inhibitor or negative control miRNA inhibitor (NCinhibitor) using Lip2000and the expression of Smad4was assessed using QRT-PCRand Western blot assays.
Results: The expression levels of miRNA-146a were notably up-regulated byBxCM in DCs compared with normal ones (P＜0.05). However, the protein level ofSmad4in BxCM-treated DCs was significantly lower than those in normal DCs (P＜0.05). Meanwhile, decreased expression of miRNA-146a caused by miRNA-146ainhibitor recovered the reduced expression of Smad4in BxCM-treated DCs and normalDCs (P＜0.05).
Conclusion: miRNA-146a negatively regulates the Smad4gene expression both inBxCM-treated DCs and normal DCs. BxCM enhanced the expression level ofmiRNA-146a and inhibited the expression of Smad4, which may contribute to its abilityto suppress maturation and function of DCs.
Part3The effects of blocking elevated miRNA-146a in BxCM-inducedDC on the maturation and immune function of DC
Objective: To investigate the role of miRNA-146a on BxCM-mediated DCphenotype and immune function change. To study the detailed mechanisms involved inthe effect of pancreatic cancer on DCs and offer the necessary theory forimmunotherapy.
Methods: miRNA-146a inhibitor or NC inhibitor were transfected in theBxCM-treated mDCs. The expressions of cell surface markers and IL-12were testedusing flow cytometry and ELISA assay. DCs were loaded with whole tumor cell antigenof BxPC-3cells. The antigen-loaded mDCs were incubated with T lymphocyte cells at aDC/T cell ratio of1:10. Interferon (INF)-γ and IL-12secretion levels were examined at24h after cell mixing using Human IFN-γ ELISPOT Kit and Human IL-12ELISAassay Kit. T lymphocyte proliferation was determined using the MTS assay afterincubation for5days. CTL response was used to investigate the effect of DCs on theactivity of tumor specific CTLs induced in vitro.
Results: Inhibition of elevated miRNA-146a significantly increased the expressionof CD1a, CD86, CD80, CD83, and HLA-DR on BxCM-treated DCs (P＜0.05),although still less than untreated DCs. There was a notably increased T cell proliferationrate and stronger CTL response in miRNA-146a inhibitor group compared with that inBxCM-treated group, although still lower than that in normal group (P＜0.05).
Conclusion: BxCM reduced phenotypic maturation and the ability of the DCs toactivate the immune response, which is partly through up-regulating miRNA-146aexpression in DCs.
引文
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